Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents

ABSTRACT

The invention relates to tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents.

This application claims the benefit of the filing date of U.S.application Ser. No. ______ (not yet assigned), Attorney Docket No.SCH-1982 filed Oct. 8, 2004, which claims the benefit of U.S. Ser. No.60/511,575 filed Oct. 16, 2003, all of which are incorporated byreference herein.

The invention relates to tetrahydronaphthalene derivatives, process fortheir production and their use as anti-inflammatory agents.

Open-chain, non-steroidal anti-inflammatory agents are known from theprior art (DE 100 38 639 and WO 02/10143). In the experiment, thesecompounds show dissociations of action between anti-inflammatory andundesirable metabolic actions and are superior to the previouslydescribed nonsteroidal glucocorticoids or exhibit at least just as goodan action.

The selectivity compared to the other steroid receptors as well as thepharmacokinetic parameters of the compounds of the prior art stillrequires improvement, however.

It was therefore the object of this invention to make availablecompounds whose selectivity compared to the other steroid receptors aswell as their pharmacokinetic properties are at least just as good orbetter than the compounds of the prior art.

This object is achieved by the compounds of this invention, explained inthe claims.

This invention therefore relates to compounds of general formula (I)

in which

-   -   R¹ and R², independently of one another, mean a hydrogen atom, a        hydroxy group, a halogen atom, an optionally substituted        (C₁-C₁₀)-alkyl group, an optionally substituted (C₁-C₁₀)-alkoxy        group, a (C₁-C₁₀)-alkylthio group, a (C₁-C₅)-perfluoroalkyl        group, a cyano group, or a nitro group, or R¹ and R² together        mean a group that is selected from the groups —O—(CH₂)_(n)—O—,        —O—(CH₂)_(n)—CH₂—, —O—CH═CH—, —(CH₂)_(n+2)—, —NH—(CH₂)_(n+1),        N(C₁-C₃-alkyl)-(CH₂)_(n+1), or —NH—N═CH—,    -    whereby n=1 or 2, and the terminal oxygen atoms and/or carbon        atoms and/or nitrogen atoms are linked to directly adjacent        ring-carbon atoms, or NR⁸R⁹,    -    whereby R⁸ and R⁹, independently of one another, can be        hydrogen, C₁-C₅-alkyl or (CO)—C₁-C₅-alkyl,    -   R³ means a C₁-C₁₀-alkyl group that optionally is substituted by        1-3 hydroxy groups, halogen atoms, 1-3 (C₁-C₅)-alkoxy groups, an        optionally substituted (C₃-C₇)-cycloalkyl group, an optionally        substituted heterocyclyl group, an optionally substituted aryl        group, a monocyclic or bicyclic heteroaryl group that optionally        contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2        sulfur atoms and/or 1-2 keto groups and that optionally is        substituted by one or more groups selected from (C₁-C₅)-alkyl        groups (which optionally can be substituted by 1-3 hydroxy        groups or 1-3 COOR¹³ groups, whereby R¹³ means hydrogen or a        C₁-C₅-alkyl group); (C₁-C₅)-alkoxy groups, halogen atoms,        hydroxy groups, NR⁸R⁹ groups, exomethylene groups, or oxygen,        whereby this group can be linked via any position to the amine        of the tetrahydronaphthalene system and optionally can be        hydrogenated at one or more locations,    -   R⁴ means a hydroxy group, a group OR¹⁰, or an O(CO)R¹⁰ group,        whereby R¹⁰ means any hydroxy protective group or a C₁-C₁₀-alkyl        group,    -   R⁵ means a (C₁₋C₁₀)-alkyl group or an optionally partially or        completely fluorinated (C₁-C₁₀)-alkyl group,    -   R⁶ and R⁷, independently of one another, mean a hydrogen atom, a        methyl or ethyl group or together with the carbon atom of the        tetrahydronaphthalene system mean a (C₃-C₆)-cycloalkyl ring.

Compounds of general formula (I),

in which

-   -   R¹ and R², independently of one another, mean a hydrogen atom, a        hydroxy group, a halogen atom, a (C₁-C₁₀)-alkyl group, a        (C₁-C₁₀)-alkoxy group, a (C₁-C₁₀)-alkylthio group, a        (C₁-C₅)-perfluoroalkyl group, a cyano group, or a nitro group,        or R¹ and R² together mean a group that is selected from the        groups —O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, —O—CH═CH—,        —(CH₂)_(n+2)—, —NH—(CH₂)_(n+1), —N(C₁-C₃-alkyl)-(CH₂)_(n+1), and        —NH—N═CH—,    -    whereby n=1 or 2, and the terminal oxygen atoms and/or carbon        atoms and/or nitrogen atoms are linked to directly adjacent        ring-carbon atoms, or NR⁸R⁹,    -    whereby R⁸ and R⁹, independently of one another, can be        hydrogen, C₁-C₅-alkyl or (CO)—C₁-C₅-alkyl,    -   R³ means a C₁-C₁₀-alkyl group that optionally can be substituted        by 1-3 hydroxy groups, halogen atoms, or 1-3 (C₁-C₅)-alkoxy        groups, an optionally substituted (C₃-C₇)-cycloalkyl group, an        optionally substituted heterocyclyl group, an optionally        substituted aryl group, a monocyclic or bicyclic heteroaryl        group that optionally contains 1-3 nitrogen atoms and/or 1-2        oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups and        that optionally is substituted by one or more groups that are        selected from (C₁-C₅)-alkyl groups (which optionally can be        substituted by 1-3 hydroxy groups or 1-3 COOR⁶ groups);        (C₁-C₅)-alkoxy groups, halogen atoms, or exomethylene groups,        whereby this group can be linked via any position to the amine        of the tetrahydronaphthalene system and optionally can be        hydrogenated at one or more locations,    -   R⁴ means a hydroxy group, or a group OR¹⁰,    -   R⁵ means a (C₁-C₅)-alkyl group or an optionally partially or        completely fluorinated (C₁-C₅)-alkyl group,    -   R⁶ and R⁷, independently of one another, mean a hydrogen atom, a        methyl or ethyl group or together with the carbon atom of the        tetrahydronaphthalene system mean a (C₃-C₆)-cycloalkyl ring,        are a subject of this invention.

Compounds of general formula (I),

in which

-   -   R¹ and R², independently of one another, mean a hydrogen atom, a        hydroxy group, a halogen atom, an optionally substituted        (C₁-C₁₀)-alkyl group, an optionally substituted (C₁-C₁₀)-alkoxy        group, a (C₁-C₁₀)-alkylthio group, a (C₁-C₅)-perfluoroalkyl        group, a cyano group, or a nitro group, or R¹ and R² together        mean a group that is selected from the groups —O—(CH₂)_(n)—O—,        —O—(CH₂)_(n)—CH₂—, —O—CH═CH—, —(CH₂)_(n)+₂—, —NH—(CH₂)_(n+1),        N(C₁-C₃-alkyl)-(CH₂)_(n+1), and —NH—N═CH—,    -    whereby n=1 or 2, and the terminal oxygen atoms and/or carbon        atoms and/or nitrogen atoms are linked to directly adjacent        ring-carbon atoms, or NR⁸R⁹,    -    whereby R⁸ and R⁹, independently of one another, can be        hydrogen, C₁-C₅-alkyl or (CO)—C₁-C₅-alkyl,    -   R³ means a monocyclic or bicyclic heteroaryl group that        optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms        and/or 1-2 sulfur atoms and/or 1-2 keto groups and that        optionally is substituted by one or more groups that are        selected from (C₁-C₅)-alkyl groups (which optionally can be        substituted by 1-3 hydroxy or 1-3 COOR¹³ groups, whereby R¹³        means hydrogen or a C₁-C₅-alkyl group); (C₁-C₅)-alkoxy groups,        halogen atoms, hydroxy groups, NR⁸R⁹ groups, exomethylene        groups, or oxygen, whereby this group can be linked via any        position to the amine of the tetrahydronaphthalene system and        optionally can be hydrogenated at one or more locations,    -   R⁴ means a hydroxy group, a group OR¹⁰ or an O(CO)R¹⁰ group,        whereby R¹⁰ means any hydroxy protective group or a C₁-C₁₀-alkyl        group,    -   R⁵ means a (C₁-C₁₀)-alkyl group or an optionally partially or        completely fluorinated (C₁-C₁₀)-alkyl group,    -   R⁶ and R⁷, independently of one another, mean a hydrogen atom, a        methyl or ethyl group, or together with the carbon atom of the        tetrahydronaphthalene system mean a (C₃-C₆)-cycloalkyl ring,        are another subject of this invention.

Compounds of general formula (I),

in which

-   -   R¹ and R², independently of one another, mean a hydrogen atom, a        hydroxy group, a halogen atom, an optionally substituted        (C₁-C₁₀)-alkyl group, an optionally substituted (C₁-C₁₀)-alkoxy        group, a (C₁-C₁₀)-alkylthio group, a (C₁-C₅)-perfluoroalkyl        group, a cyano group, or a nitro group, or R¹ and R² together        mean a group that is selected from the groups —O—(CH₂)_(n)—O—,        —O—(CH₂)_(n)—CH₂—, —O—CH═CH—, —(CH₂)_(n+2)—, —NH—(CH₂)_(n+1),        N(C₁-C₃-alkyl)-(CH₂)_(n+1), or —NH—N═CH—,    -    whereby n=1 or 2, and the terminal oxygen atoms and/or carbon        atoms and/or nitrogen atoms are linked to directly adjacent        ring-carbon atoms, or NR⁸R⁹,    -    whereby R⁸ and R⁹, independently of one another, can be        hydrogen, C₁-C₅-alkyl or (CO)—C₁-C₅-alkyl,    -   R³ means a monocyclic or bicyclic heteroaryl group that        optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms        and/or 1-2 sulfur atoms and/or 1-2 keto groups and that        optionally is substituted by one or more groups that are        selected from (C₁-C₅)-alkyl groups (which optionally can be        substituted by 1-3 hydroxy groups or 1-3 COOR¹³ groups, whereby        R¹³ means hydrogen or a C₁-C₅-alkyl group), (C₁-C₅)-alkoxy        groups, halogen atoms, hydroxy groups, NR⁸R⁹ groups,        exomethylene groups, or oxygen, whereby this group can be linked        via any position to the amine of the tetrahydronaphthalene        system and optionally can be hydrogenated at one or more        locations,    -   R⁴ means a hydroxy group, a group OR¹⁰, or an O(CO)R¹⁰ group,        whereby R¹⁰ means any hydroxy protective group or a C₁-C₁₀-alkyl        group,    -   R⁵ means an optionally partially or completely fluorinated        (C₁-C₁₀)-alkyl group,    -   R⁶ and R⁷, independently of one another, mean a hydrogen atom, a        methyl or ethyl group or together with the carbon atom of the        tetrahydronaphthalene system mean a (C₃-C₆)-cycloalkyl ring.

Compounds that on the aromatic ring of the tetrahydronaphthalene systemcarry one or two substituents, selected from the group optionallysubstituted C₁-C₅-alkyl, optionally substituted C₁-C₅-alkoxy,C₁-C₅-perfluoroalkyl, halogen, hydroxy, cyano, nitro, —O—(CH₂)_(n)—O—,—O—(CH₂)_(n)—CH₂—, —O—CH═CH—, —(CH₂)_(n+2)—, —NH—(CH₂)_(n+1, N(C)₁-C₃-alkyl)-(CH₂)_(n+1), or —NH—N═CH—, whereby n=1 or 2, are a specialsubject of the invention, and the terminal oxygen atoms and/or carbonatoms and/or nitrogen atoms are linked to directly adjacent ring-carbonatoms.

Compounds that on the aromatic ring of the tetrahydronaphthalene systemcarry one or two substituents, selected from the group C₁-C₅-alkyl,C₁-C₅-alkoxy, C₁-C₅-perfluoroalkyl, halogen, hydroxy, nitro,—O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, —O—CH═CH—, —(CH₂)_(n+2)—,—NH—(CH₂)_(n+1), N(C₁-C₃-alkyl)-(CH₂)_(n+1), or —NH—N═CH—, whereby n=1or 2, are another subject of the invention, and the terminal oxygenatoms and/or carbon atoms and/or nitrogen atoms are linked to directlyadjacent ring-carbon atoms.

The compounds in which R¹ and R² together mean the radicals—O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, —O—CH═CH—, —(CH₂)_(n+2)—,—NH—(CH₂)_(n+1), N(C₁-C₃-alkyl)-(CH₂)_(n+1), and —NH—N═CH— are asubgroup of these compounds. —O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, and—O—CH═CH— are preferred.

The compounds in which alkyl radicals R¹ and R² have the meaning—(CH₂)_(n+2)— and thus form a 5- to 6-membered ring together with thecarbon atom of the chain represent another subgroup.

Compounds of general formula I according to claim 1, in which R³ aC₁-C₁₀-alkyl group, which optionally can be substituted by 1-3 hydroxygroups, halogen atoms, 1-3 (C₁-C₅)-alkoxy groups, an optionallysubstituted (C₃-C₇)-cycloalkyl group, an optionally substitutedheterocyclyl group, a monocyclic or bicyclic heteroaryl group thatoptionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or1-2 sulfur atoms and/or 1-2 keto groups and that optionally issubstituted by one or more groups that are selected from (C₁-C₅)-alkylgroups, (C₁-C₅)-alkoxy groups, halogen atoms, and exomethylene groups,whereby these groups can be linked via any position to the amine of thetetrahydronaphthalene system and optionally can be hydrogenated at oneor more locations, are another subject of the invention.

Compounds of formula I, in which R³ means a C₁-C₁₀-alkyl group, whichoptionally can be substituted by 1-3 hydroxy groups, halogen atoms, anoptionally substituted phenyl group, a monocyclic or bicyclic heteroarylgroup that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or1-2 sulfur atoms and that optionally is substituted by 1-2 keto groups,1-2 (C₁-C₅)-alkyl groups, 1-2 (C₁-C₅)-alkoxy groups, 1-3 halogen atoms,or 1-2 exomethylene groups, whereby these groups can be linked via anyposition to the nitrogen atom of the tetrahydronaphthalene system andoptionally can be hydrogenated at one or more locations, are anothersubject of the invention.

Compounds of formula I according to claims 1 to 5, in which R³ means amonocyclic or bicyclic heteroaryl group that optionally contains 1-4nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or1-2 keto groups and that optionally is substituted by one or moregroups, independently of one another, selected from (C₁-C₅)-alkylgroups, which themselves optionally can be substituted by 1-3 hydroxygroups or 1-3 COOR¹³ groups, whereby R¹³ means hydrogen or(C₁-C₅)-alkyl; (C₁-C₅)-alkoxy groups, halogen atoms, hydroxy groups,NR⁸R⁹ groups, exomethylene groups, or oxygen, whereby this group can belinked via any position to the amine of the tetrahydronaphthalene systemand optionally can be hydrogenated at one or more locations, are apreferred subject of the invention.

Compounds of general formula I, in which R³ means a monocyclic orbicyclic heteroaryl group that optionally contains 1-4 nitrogen atomsand/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groupsand that optionally is substituted by one or more groups, independentlyof one another, selected from (C₁-C₅)-alkyl groups, which themselvesoptionally can be substituted by 1-3 hydroxy groups or 1-3 COOR¹³groups, whereby R¹³ means hydrogen or (C₁-C₅)-alkyl; (C₁-C₅)-alkoxygroups, halogen atoms, hydroxy groups, NR⁸R⁹ groups, exomethylenegroups, or oxygen, whereby this group can be linked via any position tothe amine of the tetrahydronaphthalene system and optionally can behydrogenated at one or more locations, and R⁵ means an optionallypartially or completely fluorinated (C₁-C₅)-alkyl group, are anotherpreferred subject of this invention.

Compounds of general formula I, in which R³ means a C₁-C₁₀-alkyl group,which optionally can be substituted by 1-3 hydroxy groups, halogenatoms, a phenyl, phthalidyl, isoindolyl, dihydroindolyl,dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl,phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl,indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl,phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl,dihydroisoindolonyl, benzimidazole or indolyl group that optionally issubstituted with C₁-C₅-alkyl, halogen, hydroxy, or C₁-C₅-alkoxy, are apreferred subject of the invention.

Compounds of general formula I, in which R³ a phenyl or naphthyl,phthalidyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl,isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl,quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazoleor indolyl group that optionally is substituted with C₁-C₅-alkyl,halogen, hydroxy, or C₁-C₅-alkoxy, are an also preferred subject.

Stereoisomers of general formula I or II, in which R³ means anoptionally substituted isoquinolonyl, quinolonyl, quinazolinyl,phthalazinyl, indazolyl, quinolinyl, isoquinolinyl, isoquinolonyl,dihydroindolonyl, dihydroindolyl, dihydroindolonyl, naphthyl, pyridyl,or phthalidyl group, are another subject of the invention. Stereoisomersof general formula I in which R³ means isoquinolin-1(2H)on-5yl,quinolin-2(1H)-on-5yl-, 8- or 7-fluoro-2-methyl-quinazoline,7,8-difluoro-4-methyl-quinazoline, 7,8-difluoro-2-methyl-quinazoline or2-methyl-phthalazin-1-one, are another subject of the invention.

Radical R³ is bonded via the amine to the tetrahydronaphthalene system.If radical R³ exhibits several positions that are chemically possible tobe bonded to the ring system, then this invention comprises all thesepossibilities.

Radical R³ is also part of this invention when it is hydrogenated at oneor more locations.

As substituents of the monocyclic or bicyclic heteroaryl groups(heterocyclic groups) R³, just as it was first defined, for example,hydroxy, halogen atoms, in particular fluorine and chlorine,(C₁-C₅)-alkyl groups (which themselves optionally can be substituted byhydroxy groups, (C₁-C₅)-alkoxy groups or COOR¹³ groups, whereby R¹³means hydrogen or (C₁-C₅)-alkyl), in particular methyl, (C₂-C₅)-alkenylgroups, completely or partially fluorinated (C₁-C₅)-alkyl groups, inparticular CF₃, CFH₂ or C₂F₅, (C₁-C₅)-alkoxy groups, in particularmethoxy and ethoxy, NR⁸R⁹ groups, in particular NH₂, N(CH₃)₂ or NH(CH₃),cyano groups as well as keto groups, which are formed with a carbon atomof a ring of the heteroaryl group, and oxygen, which forms an N-oxidewith an optionally present nitrogen atom of the ring, are suitable atchemically suitable positions. The group that consists of fluorine,chlorine, OH, CH₃, CF₃, CFH₂, or C₂F₅, OCH₃, OC₂H₅, NH₂, N(CH₃)₂ andNH(CH₃), cyano, keto and oxygen follows from the above as a preferredgroup of substituents for radical R³ as it is defined in claim 1 and forall additional claims.

The hydroxy group in R⁴ can be protected by one of the common hydroxyprotective groups, such as, for example, silyl ether or ester of organicC₁-C₁₀-acids or can be present as C₁-C₅-ethers or benzyl ether,preferably as one of the common hydroxy protective groups or asC₁-C₅-ether or preferably present as C₁-C₅-ether.

The hydroxy group is preferred as radical R⁴.

The common hydroxy protective groups are described in detail in T. W.Greene, P. G. M. Wuts “Protective Groups in Organic Synthesis,” 2^(nd)Edition, John Wiley & Sons, 1991).

The protective groups are preferably alkyl-, aryl- or mixedalkylaryl-substituted silyl groups, e.g., the trimethylsilyl (TMS),triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS),tert-butyldiphenylsilyl (TBDPS) or triisopropylsilyl groups (TIPS) oranother conventional hydroxy protective group (methoxymethyl,methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl, andtetrahydropyranyl groups).

Compounds of general formula I in which R⁵ means an optionally partiallyor completely fluorinated (C₁-C₅)-alkyl group, preferably a completelyfluorinated (C₁-C₅)-alkyl group, are a subject of the invention. R⁵especially preferably stands for the trifluoromethyl group or thepentafluoroethyl group.

The radicals and all their subcombinations, which are confirmed by theexamples, represent an especially preferred subgroup, as it wasdisclosed for this invention.

The designation halogen atom or halogen means a fluorine, chlorine,bromine or iodine atom. A fluorine, chlorine or bromine atom ispreferred.

The C₁-C₅-alkyl groups R¹, R², R⁴, R⁶, and R⁷ can be straight-chain orbranched and stand for a methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, tert.-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or3-methylbutyl group. A methyl or ethyl group is preferred. Theabove-mentioned alkyl groups optionally can be substituted by 1-5groups, independently of one another, selected from hydroxy, cyano,nitro, COOR¹³, C₁-C₅-alkoxy groups, halogen, NR⁸R⁹, a partially orcompletely fluorinated C₁-C₃-alkyl group; fluorine, cyano, methoxy andhydroxy groups are preferred.

They can optionally be substituted by 1-3 hydroxy groups and/or 1-3COOR¹³ groups. Hydroxy groups are preferred.

For a partially or completely fluorinated C₁-C₃-alkyl group, thefollowing partially or completely fluorinated groups are considered:fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl,tetrafluoroethyl, and pentafluoroethyl. Of the latter, thetrifluoromethyl group or the pentafluoroethyl group is preferred. Thereagents, which optionally are used during the synthesis, arecommercially available, or the published syntheses of the correspondingreagents are part of the prior art, or published syntheses can beapplied analogously.

The C₁-C₅-alkoxy groups can be straight-chain or branched and stand fora methoxy, ethoxy, n-propoxy, iso-propoxy-, n-butoxy, iso-butoxy,tert.-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or3-methylbutoxy group. A methoxy or ethoxy group is preferred. Theabove-mentioned alkoxy groups optionally can be substituted with 1-3groups that are selected from halogen, in particular fluorine, chlorine,hydroxy and cyano.

The C₁-C₅-alkylthio groups can be straight-chain or branched and standfor a methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio,iso-butylthio, tert.-butylthio or n-pentylthio, 2,2-dimethylpropylthio,2-methylbutylthio or 3-methylbutylthio group. A methylthio or ethylthiogroup is preferred.

Substituent NR⁸R⁹ means, for example, NH₂, NH(CH₃), N(CH₃)₂, NH(C₂H₅),N(C₂H₅)₂, NH(C₃H₇), N(C₃H₇)₂, NH(C₄H₉), N(C₄H₉)₂, NH(C₅H₁₁), N(C₅H₁₁)₂,NH(CO)CH₃, NH(CO)C₂H₅, NH(CO)C₃H₇, NH(CO)C₄H₉, or NH(CO)C₅H₁₁.

The cycloalkyl group means a saturated cyclic group that optionally issubstituted by one or more groups selected from hydroxy groups, halogenatoms, (C₁-C₅)-alkyl groups, (C₁-C₅)-alkoxy groups, NR⁸R⁹ groups, COOR¹³groups, CHO, and cyano, and said group has 3 to 7 ring-carbon atoms,such as, for example, cyclopropyl, methylcyclopropyl, cyclobutyl,methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl,methylcyclohexyl, cycloheptyl, and methylcycloheptyl.

The heterocyclyl group is not aromatic and can be, for example,pyrrolidine, imidazolidine, pyrazolidine, or piperidine.

As substituents for heterocyclyl and heteroaryl groups, for example,substituents from the group optionally substituted C₁-C₅-alkyl group,hydroxy-, C₁-C₅-alkoxy-, NR⁸R⁹—, halogen, cyano-, COOR¹³—, and CHO— aresuitable. The substituents can optionally also be bonded to the nitrogenatom; then N-oxides are also included in the definition.

Aryl groups in terms of the invention are aromatic or partially aromaticcarbocyclic groups with 6 to 14 carbon atoms, which exhibit a ring, suchas, e.g., phenyl or phenylene, or several condensed rings, such as,e.g., naphthyl or anthranyl. By way of example, phenyl, naphthyl,tetralinyl, anthranyl, indanyl, and indenyl can be mentioned.

The aryl groups can be substituted at any suitable position that resultsin a stable stereoisomer by one or more radicals from the group hydroxy,halogen; C₁-C₅-alkyl that optionally is substituted by 1-3 hydroxygroups or COOR¹³ groups; C₁-C₅-alkoxy, cyano, CF₃, and nitro. Theoptionally substituted phenyl group and the naphthyl group arepreferred.

The monocyclic or bicyclic heteroaryl group can optionally besubstituted by one or more substituents that are selected from theC₁-C₅-alkyl group, C₁-C₅-alkoxy group, halogen or exomethylene thatoptionally is substituted by 1-3 hydroxy groups or 1-3 COOR¹³ groups.The substituents optionally also can be directly bonded to theheteroatom. N-oxides are also included in this invention.

The monocyclic or bicyclic heteroaryl group optionally can contain 0-9groups from the group nitrogen atoms, oxygen atoms, sulfur atoms or ketogroups, of which at most 3 (4?) nitrogen atoms, at most 2 oxygen atoms,at most 2 sulfur atoms and at most 2 keto groups can be contained. Anysubcombination of these groups is possible. The heteroaryl group can behydrogenated at one or more locations.

Monocyclic heteroaryl groups can be, for example, pyridine, pyrazine,pyrimidine, pyridazine, triazine, azaindolizine, 2H— and 4H-pyran, 2H—and 4H-thiopyran, furan, thiophene, 1H— and 4H-pyrazole, 1H— and2H-pyrrole, oxazole, thiazole, furazan, 1H— and 4H-imidazole, isoxazole,isothiazole, oxadiazole, triazole, tetrazole, or thiadiazole.

Bicyclic heteroaryl groups can be, for example, a phthalidyl,thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl,indazolyl, benzothiazolyl, indolonyl, dihydroindolonyl, isoindolonyl,dihydroisoindolonyl, benzofuranyl, benzimidazolyl, dihydroisoquinolinyl,dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, quinolinyl,isoquinolinyl, quinolonyl, isoquinolonyl, quinazolinyl, quinoxalinyl,cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, cumarinyl,isocumarinyl, indolizinyl, isobenzofuranyl, azaindolyl, azaisoindolyl,furanopyridyl, furanopyrimidinyl, furanopyrazinyl, furanopyridazinyl,dihydrobenzofuranyl, dihydrofuranopyridyl, dihydrofuranopyrimidinyl,dihydrofuranopyrazinyl, dihydrofuranopyridazinyl, or dihydrobenzofuranylgroup.

If the heteroaryl groups are partially or completely hydrogenated,stereoisomers of formula I or II, in which R³ means tetrahydropyranyl,2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydropyridyl,1H-pyridin-2-onyl, 1H-pyridin-4-onyl, 4-aminopyridyl,1H-pyridin-4-ylidenaminyl, chromanyl, isochromanyl, thiochromanyl,decahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl,5,6,7,8-tetrahydro-1H-quinolin-4-onyl, decahydroisoquinolinyl,tetrahydroisoquinolinyl, dihydroisoquinolinyl,3,4-dihydro-2H-benz[1,4]oxazinyl, 1,2-dihydro[1,3]benzoxazin-4-onyl,3,4-dihydrobenz[1,4]oxazin-4-onyl, 3,4-dihydro-2H-benzo[1,4]thiazinyl,4H-benzo[1,4]thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl,1H-cinnolin-4-onyl, 3H-quinazolin-4-onyl, 1H-quinazolin-4-onyl,3,4-dihydro-1H-quinoxalin-2-onyl,2,3-1,2,3,4-tetrahydro[1,5]naphthyridinyl, dihydro-1H-[1,5]naphthyridyl,1H-[1,5]naphthyrid-4-onyl, 5,6,7,8-tetrahydro-1H-naphthyridin-4-onyl,1,2-dihydropyrido[3,2-d][1,3]oxazin-4-onyl, octahydro-1H-indolyl,2,3-dihydro-1H-indolyl, octahydro-2H-isoindolyl,1,3-dihydro-2H-isoindolyl, 1,2-dihydroindazolyl,1H-pyrrolo[2,3-b]pyridyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridyl, or2,2-dihydro-1H-pyrrolo[2,3-b]pyridin-3-onyl, are part of this invention.

The compounds of general formula I according to the invention can bepresent as stereoisomers because of the presence of asymmetry centers.All possible diastereomers (e.g.: RR, RS, SR, SS) both as racemates andin enantiomer-pure form are subjects of this invention. The termstereoisomers also comprises all possible diastereomers and regioisomersand tautomers (e.g., keto-enol tautomers), in which the stereoisomersaccording to the invention can be present, which thus are also a subjectof the invention.

The compounds according to the invention can also be present in the formof salts with physiologically compatible anions, for example in the formof hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate,fumarate, tartrate, benzoate, mesylate, citrate or succinate.

The compounds according to the invention are produced by the open-chainprecursors of general formula II being generated according to methodsthat are known in the prior art

and then being cyclized to the compounds of general formula I eitherwithout additional reagent in a solvent, preferably chlorinatedhydrocarbons, such as, e.g., methylene chloride or dichloroethane orconcentrated organic acids, preferably glacial acetic acid, or by addinginorganic or organic acids or Lewis acids under temperatures in therange of −70° C. to +80° C. (preferably in the range of −30° C. to +80°C.).

A method for the production of stereoisomers of general formula I, whichis characterized in that imines of general formula II are cyclized tothe stereoisomers of general formula I either without additional reagentin a solvent or concentrated organic acids, or by adding inorganic ororganic acids or Lewis acids under temperatures in the range of −70° C.to +80° C. (preferably in the range of −30° C. to +80° C.), as well astheir direct precursors of formula II, is thus also a subject of thisinvention.

The new imines for the cyclization are also subjects of this invention,in particular those that were disclosed by the examples.

The binding of the substances to the glucocorticoid receptor (GR) andother steroid-hormone receptors (mineral corticoid receptor (MR),progesterone receptor (PR) and androgen receptor (AR)) is examined withthe aid of recombinantly produced receptors. Cytosol preparations of Sf9cells, which had been infected with recombinant baculoviruses that codefor the GR, are used for the binding studies. In comparison to thereference substance [³H]-dexamethasone, the substances show a highaffinity to the GR. IC₅₀(GR)=95 nM and IC₅₀(PR)=460 were measured forthe compound from Example 49.

The GR-mediated inhibition of the transcription of cytokines, adhesionmolecules, enzymes and other pro-inflammatory factors is considered tobe an essential, molecular mechanism for the anti-inflammatory action ofglucocorticoids. This inhibition is produced by an interaction of the GRwith other transcription factors, e.g., AP-1 and NF-kappa-B (for asurvey, see Cato, A. C. B. and Wade, E., BioEssays 18, 371-378, 1996).

The compounds of general formula I according to the invention inhibitthe secretion of cytokine IL-8 into the human monocyte cell line THP-1that is triggered by lipopolysaccharide (LPS). The concentration of thecytokines was determined in the supernatant by means of commerciallyavailable ELISA kits. The compound of Example 49 showed an inhibitionIC₅₀(IL8)=19 nM.

The anti-inflammatory action of the compounds of general formula I wastested in the animal experiment by tests in the croton oil-inducedinflammation in rats and mice (J. Exp. Med. (1995), 182, 99-108). Tothis end, croton oil in ethanolic solution was applied topically to theanimals' ears. The test substances were also administered topically orsystemically at the same time or two hours before the croton oil. After16-24 hours, the ear weight was measured as a yardstick for inflammatoryedema, the peroxidase activity as a yardstick for the invasions ofgranulocytes, and the elastase activity as a yardstick for the invasionof neutrophilic granulocytes. In this test, the compounds of generalformula I inhibit the three above-mentioned inflammation parameters bothafter topical administration and after systemic administration.

One of the most frequent undesirable actions of a glucocorticoid therapyis the so-called “steroid diabetes” [cf., Hatz, H. J., Glucocorticoide:Immunologische Grundlagen, Pharmakologie und Therapierichtlinien,[Glucocorticoids: Immunological Bases, Pharmacology and TherapyGuidelines], Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart,1998]. The reason for this is the stimulation of gluconeogenesis in theliver by induction of the enzymes responsible in this respect and byfree amino acids, which are produced from the degradation of proteins(catabolic action of glucocorticoids). A key enzyme of the catabolicmetabolism in the liver is tyrosinamino transferase (TAT). The activityof this enzyme can be determined from liver homogenates by photometryand represents a good measurement of the undesirable metabolic actionsof glucocorticoids. To measure the TAT induction, the animals aresacrificed 8 hours after the test substances are administered, thelivers are removed, and the TAT activity is measured in the homogenate.In this test, at doses in which they have an anti-inflammatory action,the compounds of general formula I induce little or no tyrosinaminotransferase.

Because of their anti-inflammatory action, and, in addition,anti-allergic, immunosuppressive and antiproliferative action, thecompounds of general formula I according to the invention can be used asmedications for treatment or prophylaxis of the following pathologicconditions in mammals and humans: In this case, the term “DISEASE”stands for the following indications:

-   (i) Lung diseases that are accompanied by inflammatory, allergic    and/or proliferative processes:    -   Chronic, obstructive lung diseases of any origin, primarily        bronchial asthma    -   Bronchitis of different origins    -   All forms of restrictive lung diseases, primarily allergic        alveolitis,    -   All forms of pulmonary edema, primarily toxic pulmonary edema    -   Sarcoidoses and granulomatoses, especially Boeck's disease-   (ii) Rheumatic diseases/autoimmune diseases/joint diseases that are    accompanied by inflammatory, allergic and/or proliferative    processes:    -   All forms of rheumatic diseases, especially rheumatoid        arthritis, acute rheumatic fever, polymyalgia rheumatica    -   Reactive arthritis    -   Inflammatory soft-tissue diseases of other origins    -   Arthritic symptoms in the case of degenerative joint diseases        (arthroses)    -   Traumatic arthritides    -   Collagenoses of any origin, e.g., systemic lupus erythematodes,        sclerodermia, polymyositis, dermatomyositis, Sjögren's syndrome,        Still's syndrome, Felty's syndrome-   (iii) Allergies that are accompanied by inflammatory and/or    proliferative processes:    -   All forms of allergic reactions, e.g., Quincke's edema, hay        fever, insect bites, allergic reactions to pharmaceutical        agents, blood derivatives, contrast media, etc., anaphylactic        shock, urticaria, contact dermatitis-   (iv) Vascular inflammations (vasculitides)    -   Panarteritis nodosa, temporal arteritis, erythema nodosum-   (v) Dermatological diseases that are accompanied by inflammatory,    allergic and/or proliferative processes:    -   Atopic dermatitis (primarily in children)    -   Psoriasis    -   Pityriasis rubra pilaris    -   Erythematous diseases, triggered by different noxae, e.g.,        radiation, chemicals, burns, etc.    -   Bullous dermatoses    -   Diseases of the lichenoid group,    -   Pruritis (e.g., of allergic origin)    -   Seborrheal eczema    -   Rosacea    -   Pemphigus vulgaris    -   Erythema exudativum multiforme    -   Balanitis    -   Vulvitis    -   Hair loss such as alopecia greata    -   Cutaneous T-cell lymphoma-   (vi) Kidney diseases that are accompanied by inflammatory, allergic    and/or proliferative processes:    -   Nephrotic syndrome    -   All nephritides-   (vii) Liver diseases that are accompanied by inflammatory, allergic    and/or proliferative processes:    -   Acute liver cell decomposition    -   Acute hepatitis of different origins, e.g., viral, toxic,        pharmaceutical agent-induced    -   Chronic aggressive hepatitis and/or chronic intermittent        hepatitis-   (viii) Gastrointestinal diseases that are accompanied by    inflammatory, allergic and/or proliferative processes:    -   Regional enteritis (Crohn's disease)    -   Colitis ulcerosa    -   Gastritis    -   Reflux esophagitis    -   Ulcerative colitis of other origins, e.g., native sprue-   (ix) Proctologic diseases that are accompanied by inflammatory,    allergic and/or proliferative processes:    -   Anal eczema    -   Fissures    -   Hemorrhoids    -   Idiopathic proctitis-   (x) Eye diseases that are accompanied by inflammatory, allergic    and/or proliferative processes:    -   Allergic keratitis, uveitis, iritis    -   Conjunctivitis    -   Blepharitis    -   Optic neuritis    -   Chorioiditis    -   Sympathetic ophthalmia-   (xi) Diseases of the ear-nose-throat area that are accompanied by    inflammatory, allergic and/or proliferative processes:    -   Allergic rhinitis, hay fever    -   Otitis externa, e.g., caused by contact dermatitis, infection,        etc.    -   Otitis media-   (xii) Neurological diseases that are accompanied by inflammatory,    allergic and/or proliferative processes:    -   Cerebral edema, primarily tumor-induced cerebral edema    -   Multiple sclerosis    -   Acute encephalomyelitis    -   Meningitis    -   Various forms of convulsions, e.g., infantile nodding spasms-   (xiii) Blood diseases that are accompanied by inflammatory, allergic    and/or proliferative processes:    -   Acquired hemolytic anemia    -   Idiopathic thrombocytopenia-   (xiv) Tumor diseases that are accompanied by inflammatory, allergic    and/or proliferative processes:    -   Acute lymphatic leukemia    -   Malignant lymphoma    -   Lymphogranulomatoses    -   Lymphosarcoma    -   Extensive metastases, mainly in breast, bronchial and prostate        cancers-   (xv) Endocrine diseases that are accompanied by inflammatory,    allergic and/or proliferative processes:    -   Endocrine orbitopathy    -   Thyreotoxic crisis    -   De Quervain's thyroiditis    -   Hashimoto's thyroiditis    -   Basedow's disease-   (xvi) Organ and tissue transplants, graft-versus-host disease-   (xvii) Severe shock conditions, e.g., anaphylactic shock, systemic    inflammatory response syndrome (SIRS)    -   (xviii) Substitution therapy in:    -   Innate primary suprarenal insufficiency, e.g., congenital        adrenogenital syndrome    -   Acquired primary suprarenal insufficiency, e.g., Addison's        disease, autoimmune adrenalitis, meta-infective tumors,        metastases, etc.    -   Innate secondary suprarenal insufficiency, e.g., congenital        hypopituitarism    -   Acquired secondary suprarenal insufficiency, e.g.,        meta-infective tumors, etc.-   (xix) Vomiting that is accompanied by inflammatory, allergic and/or    proliferative processes:    -   e.g., in combination with a 5-HT3 antagonist in        cytostatic-agent-induced vomiting-   (xx) Pains of inflammatory origins, e.g., lumbago.

Moreover, the compounds of general formula I according to the inventioncan be used for treatment and prophylaxis of additional pathologicconditions that are not mentioned above, for which syntheticglucocorticoids are now used (see in this respect Hatz, H. J.,Glucocorticoide: Immunologische Grundlagen, Pharmakologie undTherapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH,Stuttgart, 1998).

All previously mentioned indications (i) to (xx) are described in moredetail in Hatz, H. J., Glucocorticoide: Immunologische Grundlagen,Pharmakologie und Therapierichtlinien, WissenschaftlicheVerlagsgesellschaft mbH, Stuttgart, 1998.

For the therapeutic actions in the above-mentioned pathologicconditions, the suitable dose varies and depends on, for example, theactive strength of the compound of general formula I, the host, the typeof administration, and the type and severity of the conditions that areto be treated, as well as the use as a prophylactic agent or therapeuticagent.

In addition, the invention provides:

-   -   (i) The use of one of the compounds of formula I according to        the invention or mixture thereof for the production of a        medication for treating a DISEASE;    -   (ii) A process for treating a DISEASE, said process comprises an        administration of an amount of the compound according to the        invention, whereby the amount suppresses the disease and whereby        the amount of compound is given to a patient who requires such a        medication;    -   (iii) A pharmaceutical composition for treating a DISEASE, said        treatment comprises one of the compounds according to the        invention or mixture thereof and at least one pharmaceutical        adjuvant and/or vehicle.

In general, satisfactory results can be expected in animals when thedaily doses comprise a range of 1 μg to 100,000 μg of the compoundaccording to the invention per kg of body weight. In the case of largermammals, for example the human, a recommended daily dose lies in therange of 1 μg to 100,000 μg per kg of body weight. Preferred is a doseof 10 to 30,000 μg per kg of body weight, and more preferred is a doseof 10 to 10,000 μg per kg of body weight. For example, this dose issuitably administered several times daily. For treating acute shock(e.g., anaphylactic shock), individual doses can be given that aresignificantly above the above-mentioned doses.

The formulation of the pharmaceutical preparations based on the newcompounds is carried out in a way that is known in the art by the activeingredient being processed with the vehicles, fillers, substances thatinfluence decomposition, binding agents, moisturizers, lubricants,absorbents, diluents, flavoring correctives, coloring agents, etc., thatare commonly used in galenicals and converted into the desired form ofadministration. In this case, reference is made to Remington'sPharmaceutical Science, 15^(th) Edition, Mack Publishing Company, EastPennsylvania (1980).

For oral administration, especially tablets, coated tablets, capsules,pills, powders, granulates, lozenges, suspensions, emulsions orsolutions are suitable.

For parenteral administration, injection and infusion preparations arepossible.

For intra-articular injection, correspondingly prepared crystalsuspensions can be used.

For intramuscular injection, aqueous and oily injection solutions orsuspensions and corresponding depot preparations can be used.

For rectal administration, the new compounds can be used in the form ofsuppositories, capsules, solutions (e.g., in the form of enemas) andointments both for systemic and for local treatment.

For pulmonary administration of the new compounds, the latter can beused in the form of aerosols and inhalants.

For local application to eyes, outer ear channels, middle ears, nasalcavities, and paranasal sinuses, the new compounds can be used as drops,ointments and tinctures in corresponding pharmaceutical preparations.

For topical application, formulations in gels, ointments, fattyointments, creams, pastes, powders, milk and tinctures are possible. Thedosage of the compounds of general formula I should be 0.01%-20% inthese preparations to achieve a sufficient pharmacological action.

The invention also comprises the compounds of general formula Iaccording to the invention as therapeutic active ingredients. Inaddition, the compounds of general formula I according to the inventionare part of the invention as therapeutic active ingredients togetherwith pharmaceutically compatible and acceptable adjuvants and vehicles.

The invention also comprises a pharmaceutical composition that containsone of the pharmaceutically active compounds according to the inventionor mixtures thereof or a pharmaceutically compatible salt thereof and apharmaceutically compatible salt or pharmaceutically compatibleadjuvants and vehicles.

EXPERIMENTS Example 14-{[8-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one4-Amino-2,3-dihydroisoindol-1-one 2-Methyl-3-nitrobenzoic acid methylester

30 g (165.6 mmol) of 2-methyl-3-nitrobenzoic acid is added to 150 ml ofmethanol, and it is refluxed for two days after 2.9 ml of concentratedsulfuric acid is added. After cooling, the crystallizate (25.55 g=79%)is suctioned off and thus incorporated into the next stage.

¹H-NMR (300 MHz, DMSO-d₆): δ=2.50 (3H), 3.85 (3H), 7.56 (1H), 8.00 (1H),8.05 (1H).

2-(Bromomethyl)-3-nitrobenzoic acid methyl ester

25.55 g (130.9 mmol) of 2-methyl-3-nitrobenzoic acid methyl ester isadded to 300 ml of carbon tetrachloride, and mixed with 25.6 g (141.7mmol) of N-bromosuccinimide and 62.8 mg of benzoyl peroxide. After sevendays of refluxing, the succinimide is suctioned off after cooling, andthen the filtrate is spun in until a dry state is reached. The desiredcompound that is incorporated in crude form into the next stage remains.

¹H-NMR (300 MHz, CDCl₃): δ=4.00 (3H), 5.66 (2H), 7.55 (1H), 7.95 (1H),8.10 (1H).

2-(Azidomethyl)-3-nitrobenzoic acid methyl ester

10 g (36.5 mmol) of 2-(bromomethyl)-3-nitrobenzoic acid methyl ester ismixed with 36 ml of N,N-dimethylformamide and 24 ml of water. After 3.54g of sodium azide is added, the batch is stirred overnight. The reactionmixture is diluted with methyl-tert butyl ether, and washed twice withwater and once with brine. After drying on sodium sulfate, it isfiltered, and the solvent is spun off. The desired azide is obtained ina yield of 89.6% (7.72 g) and further incorporated in crude form.

¹H-NMR (300 MHz, CDCl₃): δ=4.00 (3H), 4.93 (2H), 7.58 (1H), 7.96 (1H),8.12 (1H).

4-Amino-2,3-dihydroisoindol-1-one

1 g (4.2 mmol) of 2-(azidomethyl)-3-nitrobenzoic acid methyl ester isadded to 10 ml of ethanol and 2 ml of glacial acetic acid and mixed with148.5 mg of Pd/C. After stirring overnight at room temperature underhydrogen atmosphere, the catalyst is suctioned off via a glass-fiberfilter, and the filtrate is evaporated to the dry state. The residue ischromatographed on a Flashmaster (mobile solvent). 391.5 mg (62.4%) ofthe desired compound is isolated.

¹H-NMR (300 MHz, DMSO-d₆): δ=4.10 (2H), 5.36 (2H), 6.75 (1H), 6.85 (1H),7.15 (1H), 8.35 (1H).

4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanal

6.55 g (21.11 mmol) ofrac-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl)-pentane-1,2-diol(WO 00/32584) is dissolved in 224 ml of dichloromethane and mixed atroom temperature with 74 ml of dry dimethyl sulfoxide and 10.68 g(105.55 mmol) of triethylamine. At 15 to 18° C., 10.08 g (63.33 mmol) ofthe SO₃/pyridine complex is added in portions within 40 minutes. Afterbeing stirred overnight at room temperature, 84 ml of saturated ammoniumchloride solution is added. A slight heating occurs. After 15 minutes ofstirring at room temperature, it is extracted twice with 300 ml each ofdiethyl ether. The organic phases are washed with water and brine anddried (sodium sulfate). After the solvent is filtered off and after thesolvent is spun off, the remaining residue is chromatographed on silicagel (mobile solvent ethyl acetate/hexane). 5.85 g (90%) of the desiredcompound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (3H), 1.46 (3H), 2.22 (1H), 3.38 (1H),3.59 (1H), 3.86 (1H), 6.70-6.80 (1H), 6.82-6.97 (2H), 9.05 (1H).

4-{[(4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidene]amino}2,3-dihydroisoindol-1-one

400 mg (1.297 mmol) ofrac-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanalis stirred with 192.1 mg (1.297 mmol) of4-amino-2,3-dihydroisoindol-1-one in 1.89 ml of glacial acetic acid forfour days at room temperature. The mixture is mixed three times withtoluene and evaporated to the dry state in a rotary evaporator. Theresidue is chromatographed on silica gel (mobile solvent ethylacetate/hexane). 429.7 mg (75.5%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.37 (3H), 1.52 (3H), 2.22 (1H), 3.42 (1H),3.84 (3H), 4.37 (2H), 4.68 (1H), 6.53-6.68 (3H), 6.72-6.95 (2H), 7.37(1H), 7.49 (1H), 7.75 (1H).

4-{[8-Fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one(Diastereomer A); 4-{[8-Fluoro-2,5dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one(Diastereomer A);4-{[8-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one(Diastereomer B)

420 mg (0.958 mmol) of the compound4-{[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}-2,3-dihydroisoindol-1-onethat is described in the paragraph above is mixed with 9.6 ml of a 1 Msolution of boron tribromide in dichloromethane, and it is stirred for1¾ hours at room temperature. The reaction mixture is mixed drop by dropwith saturated sodium bicarbonate at −30° C., specifically up to pH 8.After dilution with ethyl acetate, the cold bath is removed and stirredvigorously for 15 minutes. After 2× extraction with ethyl acetate, theorganic phases are washed with water and saturated sodium chloridesolution. After the solvent is dried (sodium sulfate) and spun off, theresidue is chromatographed on a Flashmaster (silica gel, NH₂ phase)(mobile solvent dichloromethane/methanol). 67.7 mg (16.6%) of4-{[8-fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one(diastereomer A, F1); 12.9 mg (3.2%) of 4-{[8-fluoro-2,5dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one(diastereomer A, F2), and 32.2 mg (7.9%) of4-{[8-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one(diastereomer B, F3) are isolated.

F1: ¹H-NMR (300 MHz, MeOD): δ=1.47 (3H), 1.60 (3H), 2.07 (1H), 2.25(1H), 3.49 (3H), 4.19-4.40 (2H), 5.20 (1H), 6.31 (1H), 7.00 (1H),7.15-7.30 (2H), 7.38 (1H).

F2: ¹H-NMR (300 MHz, MeOD): δ=1.50 (3H), 1.59 (3H), 2.05 (1H), 2.28(1H), 4.20-4.42 (2H), 5.18 (1H), 6.61 (1H), 6.80-6.90 (1H), 7.15 (1H),7.20-7.40 (2H).

F3: ¹H-NMR (300 MHz, MeOD): δ=1.52 (3H), 1.69 (3H), 2.03 (1H), 2.23(1H), 4.20-4.39 (2H), 5.18 (1H), 6.65-6.80 (2H), 7.10-7.23 (2H), 7.35(1H).

Example 25-{[7-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one5-Amino-isoquinolin-1(2H)-one 5-Nitroisocoumarin

16.4 g (84.03 mmol) of the 2-methyl-3-nitrobenzoic acid methyl esterthat is described under Example 1 is stirred with 26.8 g (225.1 mmol) ofN,N-dimethylformamide dimethyl acetal in 85 ml of dimethylformamide for12 hours at 130° C. The solvent is drawn off in a rotary evaporator, theresidue is taken up in methyl tert-butyl ether and washed three timeswith water. After washing with saturated NaCl solution, the organicphase is dried. After the desiccant is filtered off and the solvent isspun off, the remaining residue is chromatographed on silica gel (mobilesolvent ethyl acetate/hexane). 8.73 g (54.4%) of the desired compound isisolated.

¹H-NMR (300 MHz, CDCl₃): δ=7.39 (1H), 7.45 (1H), 7.68 (1H), 8.49 (1H),8.65 (1H).

5-Nitroisoquinolin-1(2H)-one

2.51 g (13.13 mmol) of 5-nitroisocoumarin is added in 100 ml of ethanol.Ammonia is pressure-forced in in an autoclave. The product precipitatesand is suctioned off. 1.98 g (79.7%) of the desired compound isisolated.

¹H-NMR (300 MHz, DMSO-d₆): δ=6.97 (1H), 7.45 (1H), 7.65 (1H), 8.43 (1H),8.57 (1H), 11.5 (1H).

5-Aminoisoquinolin-1(2H)-one

268.3 mg (1.51 mmol) of 5-nitroisoquinolin-1(2H)-one is added with 376.5mg of ammonium chloride and 2.6 ml of water in 14 ml of ethanol and 5.4ml of tetrahydrofuran. After addition in portions of 1.23 g of zincpowder (heating to 30 to 35° C.), it is stirred for two hours. Thereaction mixture is suctioned off through a glass-fiber filter andrewashed with ethyl acetate. After the filtrate is washed with water andsaturated sodium chloride solution, the organic phase is dried as usual.Filtering off the desiccant and spinning off the solvent produce 196.5mg (88.1%) of the desired amine.

¹H-NMR (300 MHz, DMSO-d₆): δ=5.6 (2H), 6.68 (1H), 6.87.45 (1H), 7.00(1H), 7.17 (1H), 7.39 (1H), 11.7 (1H).

4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol

A solution of 3 g of 2-hydroxy-4-methylene-2-(trifluoromethyl)valericacid ethyl ester in 22 ml of 3-chloroanisole is mixed at roomtemperature in portions with aluminum trichloride. After 48 hours ofstirring at room temperature, the batch is mixed with 2N hydrochloricacid and hexane, and it is stirred for another hour. After washing with2N hydrochloric acid and water, excess 3-chloroanisole is distilled offin a vacuum. The remaining residue is purified by chromatography onsilica gel (mobile solvent hexane/ethyl acetate). 2.85 g of a mixture of4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valericacid ethyl ester and the regioisomeric compound4-(2-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valericacid ethyl ester is obtained as a yellow oil. This substance mixture ismixed in 90 ml of ether at 0° C. with 445 mg of lithium aluminum hydrideand stirred for 12 hours. The batch is added to saturated sodiumbicarbonate solution and filtered through diatomaceous earth. The phasesare separated, and the aqueous phase is extracted with ethyl acetate. Itis washed with water and brine, dried with sodium sulfate andconcentrated by evaporation in a vacuum. After chromatography on silicagel (mobile solvent hexane/ethyl acetate), 1.87 g of the desiredcompound4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-olas a first fraction and 160 mg of the regioisomeric compound4-(2-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-olas a second fraction are obtained as colorless oils.

1st Fraction: ¹H-NMR (CDCl₃), δ=1.41 (3H), 1.51 (3H), 2.24 (1H), 2.51(1H), 2.84 (1H), 3.36 (1H), 3.48 (1H), 3.85 (3H), 6.88 (1H), 6.92 (1H),7.24 (1H).

2nd Fraction: ¹H-NMR (CDCl₃), δ=1.52 (3H), 1.62 (3H), 2.18 (1H), 2.76(1H), 2.93 (1H), 3.33 (1H), 3.55 (1H), 3.80 (3H), 6.78 (1H), 6.90 (1H),7.38 (1H).

4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal

854.6 mg (6.733 mmol) of oxalyl chloride in 14.5 ml of dichloromethaneis introduced into a heated flask. At −70° C., 1.05 ml of DMSO,dissolved in 3 ml of dichloromethane, is added in drops, and the batchis stirred for five more minutes. Then, 2 g (6.12 mmol) of4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentan-1-ol,dissolved in six milliliters of dichloromethane, is added in drops.After 20 minutes of stirring, the batch is carefully mixed with 4.24 ml(30.61 mmol) of triethylamine, specifically in a temperature range ofbetween −70 and −60° C. After five minutes of stirring at −70° C., thereaction mixture is allowed to slowly come to room temperature. 25 ml ofwater is added, and the batch is stirred for another hour at roomtemperature. After phase separation, the aqueous phase is shaken oncewith 100 ml of dichloromethane. The combined organic extracts are washedwith 1% sulfuric acid, 5% sodium bicarbonate solution and brine.According to the conventional procedure, 1.92 g (96.9%) of the desiredaldehyde is obtained, which is incorporated in crude form into the nextstage.

¹H-NMR (300 MHz, CDCl₃): δ=1.37 (3H), 1.45 (3H), 2.22 (1H), 3.35 (1H),3.59 (1H), 3.90 (3H), 6.80-6.92 (2H), 7.04 (1H), 9.02 (1H).

5-{[4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentylidene]amino}isoquinolin-1(2H)-one

300 mg (0.924 mmol) of4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanalis stirred with 148 mg (0.924 mmol) of 5-amino-isoquinolin-1-one in 1.33ml of glacial acetic acid for four days at room temperature. The mixtureis mixed three times with toluene and evaporated to the dry state in arotary evaporator. The residue is chromatographed on silica gel (mobilesolvent ethyl acetate/hexane). 382.4 mg (88.6%) of the desired compoundis isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.37 (3H), 1.58 (3H), 2.26 (1H), 3.43 (1H),3.85 (3H), 4.80 (1H), 6.43 (1H), 6.59 (1H), 6.70-6.77 (2H), 7.00 (1H),7.15-7.25 (1H), 7.30-7.45 (2H), 8.32 (1H), 11.00 (1H).

5-{[7-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one

50 mg (0.107 mmol) of the compound5-{[4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}-2,3-isoquinolin-1-onethat is described in the paragraph above is mixed at −20° C. with 2.1 mlof a 1 M solution of boron tribromide in dichloromethane, and it isstirred for two and one-half hours in a temperature range of between−20° C. and 0° C. The reaction mixture is mixed drop by drop at −20° C.with saturated sodium bicarbonate solution. After dilution with ethylacetate, the batch is allowed to come to room temperature, stirred for15 minutes and extracted twice with ethyl acetate. The combined organicextracts are washed with water and saturated NaCl solution. After dryingon sodium sulfate, the solvent is spun off, and the remaining residue ischromatographed on silica gel (mobile solvent ethyl acetate/hexane).12.5 mg (25%) of the desired compound is isolated.

¹H-NMR (300 MHz, MeOD): δ=1.55 (3H), 1.65 (3H), 2.03-2.20 (2H), 5.13(1H), 6.73 (1H), 6.80 (1H), 6.87 (1H), 7.09 (1H), 7.19 (1H), 7.40 (1H),7.70 (1H).

Example 3(+)-6-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-dioland(−)-6-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol2,6-Difluoroanisole

20 g (153.74 mmol) of 2,6-difluorophenol is dissolved in 200 ml ofacetone and mixed under nitrogen with 42.5 g (307.48 mmol) of potassiumcarbonate. After 19.1 ml of methyl iodide (2 equivalents) is added, itis refluxed for three and one-half hours. After cooling, the reactionmixture is filtered, the filter residue is washed with acetone, and thefiltrate is spun in until a dry state is reached. The residue ischromatographed on silica gel (mobile solvent ethyl acetate/hexane).17.27 g (77.9%) of the desired product is obtained. It should be notedthat the product is slightly volatile. The bath temperature should notexceed 30° C., and the vacuum of the rotary evaporator is to be adapted.

¹H-NMR (300 MHz, CDCl₃): δ=4.00 (3H), 6.80-7.00 (3H).

2-(3-Fluoro-2-methoxyphenyl)-2-methylpropanenitrile

10 g (69.39 mol) of 2,6-difluoroanisole is dissolved in 200 ml oftoluene and mixed at room temperature with 5.75 g (83.27 mmol) ofisobutyric acid nitrile. 166.5 ml of a 0.5 molar solution of potassiumhexamethyldisilazide in toluene is added in drops within 35 minutes. Inthis case, a slight temperature rise to 27.5° C. takes place. After 16hours of stirring at room temperature, the reaction mixture is mixedwith 200 ml of water and 400 ml of ethyl acetate and acidified with 10%sulfuric acid to a pH of 4. The organic phase is separated, and theaqueous phase is shaken once with ethyl acetate (200 ml). The combinedorganic extracts are shaken with water and brine. After the solvent isdried, filtered and spun off, the residue is chromatographed on silicagel (mobile solvent ethyl acetate/hexane). 7.66 g (57.1%) of the desiredcompound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.76 (6H), 4.08 (3H), 6.95-7.13 (3H).

2-(3-Fluoro-2-methoxyphenyl)-2-methylpropanal

7.66 g (39.64 mmol) of the above-described nitrile is dissolved in 158ml of toluene. At −65 to −60° C., 49.5 ml of a 1.2 molar solution ofDIBAH in toluene is added in drops within 40 minutes. After one hour ofstirring at this temperature, the dropwise addition of 493 ml of a 10%L-(+)-tartaric acid solution is begun. After 100 milliliters, thetemperature is increased to −10° C. The remainder of the tartaric acidsolution is quickly added, and the batch is stirred vigorously for twohours at room temperature. The reaction mixture is shaken twice with 400ml each of diethyl ether. The combined organic extracts are shaken withwater and brine, dried, and the solvent is spun off. The residue that isobtained (7.8 g=102%) is incorporated in crude form into the next stage.

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (6H), 3.88 (3H), 6.95-7.10 (3H), 9.60(1H).

(E/Z)-4-(3-Fluoro-2-methoxyphenyl)-4-methylpent-2-enoic acid ethyl ester

21.3 ml of a 2 molar LDA solution in THF is added in drops at 0° C. to asolution of 9.87 g (39.75 mmol) of 2-ethoxy-phosphonoacetic acidtriethyl ester in 40 ml of absolute THF. After 30 minutes of stirring at0° C., 7.8 g (39.75 mmol) of2-(3-fluoro-2-methoxyphenyl)-2-methylpropanal, dissolved in 26 ml ofTHF, is quickly added in drops at 0° C. The cold bath is removed, andthe batch is stirred for 16 hours at room temperature. The reactionmixture is poured into water and extracted twice with ethyl acetate. Thecombined organic extracts are washed with water and brine, dried, andthe solvent is spun off after the desiccant is filtered off. The residueis chromatographed on silica gel (mobile solvent ethyl acetate/hexane).8.39 g (68.2%) of the desired compound is isolated.

MS (CI): 328 (29%), 265 (100%), 181 (56%), 167 (42%).

(E/Z)-4-(3-Fluoro-2-methoxyphenyl)-4-methylpent-2-enoic acid

8.39 g (27.03 mmol) of(E/Z)-4-(3-fluoro-2-methoxyphenyl)-4-methylpent-2-enoic acid ethyl esteris mixed with 270 ml of 1N NaOH in ethanol/water (2:1) and stirred fortwo days at room temperature. The ethanol is drawn off in a rotaryevaporator, and the residue is extracted twice with 150 ml each ofdiethyl ether. The combined organic extracts are washed with water anddiscarded after TLC monitoring. The aqueous phases are acidifed to a pHof 3 with concentrated hydrochloric acid and extracted twice with 300 mleach of diethyl ether. The ether extracts are washed with water andbrine, dried, the solvent is spun off, and the residue (5.89 g=77.2%) isincorporated in crude form into the next stage.

MS (CI): 300 (100%), 282 (10%),237 (27%), 167 (26%).

4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid

5.89 g (20.86 mmol) of(E/Z)-4-(3-fluoro-2-methoxyphenyl)-4-methylpent-2-enoic acid is mixed atroom temperature with 126 ml of a 1 molar sulfuric acid, and after 21 mlof glacial acetic acid is added, it is stirred for 15 hours at a bathtemperature of 90° C. While being cooled in an ice bath, the reactionmixture is carefully mixed (heavily foaming) with solid potassiumcarbonate until a pH of 9 is reached. It is extracted twice with diethylether. The combined organic extracts are washed with water and discardedafter TLC. The combined aqueous phases are acidified with concentratedhydrochloric acid until a pH of 4 is reached, and extracted twice with300 ml each of diethyl ether. The ether extracts are washed with waterand brine, dried, and the solvent is spun off. Since the residue stillcontains acetic acid, it is spun off twice with 100 ml each of toluene.The remaining residue (4.14 g=78.1%) is incorporated in crude form intothe next stage.

¹H-NMR (300 MHz, CDCl₃): δ=1.50 (6H), 3.53 (2H), 3.93 (3H), 6.90-7.10(3H).

4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester

4.14 g (16.28 mmol) of4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid is dissolvedin 97 ml of ethanol, mixed with 1.79 ml of sulfuric acid and refluxedfor four hours. The ethanol is drawn off in a rotary evaporator, and theresidue is carefully mixed with saturated sodium bicarbonate solutionuntil a pH of 9 is reached. It is extracted twice with 100 ml each ofethyl acetate, and the combined organic extracts are washed with waterand then with brine. After the desiccant is dried and filtered off, andafter the solvent is spun in, the residue is chromatographed on silicagel (mobile solvent ethyl acetate/hexane). 4.16 g (90.6%) of the desiredcompound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.29 (3H), 1.48 (6H), 3.40 (2H), 3.98 (3H),6.89-7.09 (3H).

4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentanoicacid ethyl ester

4.16 g (14.74 mmol) of4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl esteris dissolved in 24 ml of THF and mixed at 0° C. with 2.51 g (17.68 mmol)of (trifluoromethyl)-trimethylsilane and 36.1 mg of tetrabutylammoniumfluoride. After two and one-half hours of stirring between 0 and 5° C.,the batch is poured into 50 ml of ice water. It is extracted twice with150 ml each of diethyl ether, and the combined organic extracts areworked up as usual. After chromatography on silica gel (mobile solventethyl acetate/hexane), 5.24 g (83.8%) of the desired compound isobtained.

MS (CI): 442 (100%), 425 (41%).

4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentan-1-ol

5.24 g (12.34 mmol) of4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-2-trimethylsilyloxy-pentanoicacid ethyl ester is dissolved in 45 ml of diethyl ether and mixed at 0to 5° C. in portions with 936.9 mg (24.69 mmol) of LiAlH₄. After fourand one-half hours of stirring at room temperature, the reaction mixtureis carefully mixed with saturated NaHCO₃ while being stirred in an icebath, stirred for one hour under cold conditions and overnight at roomtemperature. After the conventional working-up, 4.11 g (87.1%) of amixture that consists of the desired compound and the compound isobtained, in which the silyl ether has migrated. The mixture isincorporated in crude form into the next stage.

4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentan-1-ol

4.11 g (10.75 mmol) of4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-2-trimethylsilyloxy-pentan-1-olis dissolved in 61 ml of THF, mixed with 3.39 g (10.746 mmol) of Bu₄NFtrihydrate, and stirred for one hour at room temperature. The reactionmixture is poured into water and extracted twice with diethyl ether. Theorganic phases are washed as usual with water and brine. After thedesiccant is dried and filtered off, and after the solvent is spun in,the remaining residue is chromatographed on silica gel (mobile solventethyl acetate/hexane). 2.71 g (81.4%) of the desired compound isisolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.45 (3H), 1.54 (3H), 2.20 (1H), 2.54 (1H),2.90 (1H), 3.30-3.50 (2H), 3.98 (3H), 6.90-7.13 (3H).

4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal

765 mg (6.03 mmol) of oxalyl chloride in 13 ml of dichloromethane isintroduced into a heated flask. At −78° C., 0.855 ml of DMSO, dissolvedin 2.5 ml of dichloromethane, is added in drops, and the batch isstirred for five more minutes. Then, 1.7 g (5.48 mmol) of4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanol,dissolved in five milliliters of dichloromethane, is added in drops.After 15 minutes of stirring, the batch is carefully mixed with 3.79 ml(27.40 mmol) of triethylamine, stirred for five minutes at −78° C. andthen allowed to come slowly to room temperature. 20 ml of water isadded, and the batch is stirred for another hour at room temperature.After phase separation, the aqueous phase is shaken once with 100 ml ofdichloromethane. The combined organic extracts are washed with 1%sulfuric acid, 5% sodium bicarbonate solution and brine. After theconventional procedure, 1.617 g (96.2%) of aldehyde is obtained, whichis incorporated in crude form into the next stage.

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (3H), 1.49 (3H), 2.29 (1H), 3.29 (1H),3.59 (1H), 4.00 (3H), 6.85-7.08 (3H), 9.13 (1H).

1,1,1-Trifluoro-4-(3-fluoro-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol

1.46 g (4.746 mmol) of4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanalis stirred with 632 mg (4.746 mmol) of 4-aminoindazole in 6.78 ml ofglacial acetic acid for two days at room temperature. The reactionmixture is drawn off three times with toluene in a rotary evaporator,and the residue is chromatographed on silica gel (mobile solvent ethylacetate/hexane). 1.47 g (73.5%) of the desired compound is isolated.

MS (ES+): 424 (100%).

(+)-6-Fluoro-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-oland(−)-6-Fluoro-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

1.32 g (3.117 mmol) of the above-described imine,1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol,is dissolved in 22.8 ml of dichloromethane. 9.35 ml of a 1 M solution ofTiCl₄ in dichloromethane (3 equivalents) is added to this solution at−30° C., specifically under nitrogen within 15 minutes. The reactionmixture is stirred for three and one-half hours at −30 to −15° C. Thebatch is mixed drop by drop with saturated sodium bicarbonate solutionat −30° C. After dilution with ethyl acetate, it is stirred for 15minutes at room temperature. After 2× extraction with 150 ml each ofethyl acetate, the organic phases are washed (water, brine), dried(Na₂SO₄), and the solvent is spun off. After chromatography on silicagel (mobile solvent dichloromethane/methanol), 1.07 g (81.1%) of thedesired product is obtained as a racemate. The product is separated intoits enantiomers (Chiralpak AD 5μ; mobile solvent hexane/ethanol). The(+)-enantiomer shows an angle of rotation of [α]_(D)=+1.6° (c=1, MeOH),and the (−)-enantiomer shows an angle of rotation of [α]_(D)=−1.3° (c=1,MeOH).

(+)-6-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

200 mg (0.472 mmol) of the above-described(+)-6-fluoro-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-olis mixed at room temperature with 4.7 ml of a 1 M solution of BBr₃ indichloromethane and stirred for three and one-half hours at roomtemperature. The reaction mixture is mixed drop by drop with saturatedsodium bicarbonate solution at −30° C., specifically until a pH of 8 isreached. After dilution with ethyl acetate, the cold bath is removed,and the batch is stirred vigorously for 15 minutes. After 2× shakingwith ethyl acetate, the combined organic extracts are washed with waterand saturated brine. After drying on sodium sulfate, and after thesolvent is filtered and spun off, the residue is chromatographed onsilica gel (mobile solvent dichloromethane/methanol). 171.3 mg (88.6%)of the desired compound is obtained. The angle of rotation, measured atroom temperature, is [α]_(D)=+7.3 (c=1, MeOH).

(−)-6-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

200 mg (0.472 mmol) of the above-described(−)-6-fluoro-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-olis mixed at room temperature with 4.7 ml of a 1 M solution of BBr₃ indichloromethane and stirred for three and three-quarters hours at roomtemperature. The reaction mixture is mixed drop by drop at −30° C. withsaturated sodium bicarbonate solution, specifically until a pH of 8 isreached. After dilution with ethyl acetate, the cold bath is removed,and the batch is stirred vigorously for 15 minutes. After 2× shakingwith ethyl acetate, the combined organic extracts are washed with waterand saturated brine. After drying on sodium sulfate, and after thesolvent is filtered and spun off, the residue is chromatographed onsilica gel (mobile solvent dichloromethane/methanol). 179.4 mg (92.8%)of the desired compound is obtained. The angle of rotation, measured atroom temperature, is [α]_(D)=−7.8 (c=1, MeOH).

Example 44-{[8-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-fluoro-2,3-dihydroisoindol-1-one4-Amino-6-fluoro-2,3-dihydroisoindol-1-one2-Methyl-5-fluoro-3-nitrobenzoic acid

116 ml of sulfuric acid is introduced and mixed in portions at −15° C.with 14.70 g (95.37 mmol) of 5-fluoro-2-methylbenzoic acid. A mixture ofnitrating acid (4.79 ml of fuming nitric acid and 21.8 ml ofconcentrated sulfuric acid) is added in drops to this mixture,specifically at −15 to −10° C. during a period of 90 minutes. Afterthree more hours of stirring, the reaction mixture is poured into icewater and stirred vigorously for about one-half hour. The precipitatedcrystallizate is suctioned off, washed neutral with water and dried. Theyield is 8.56 g (45.1%) of a mixture of various regioisomers andby-products. This mixture is incorporated into the next stage(esterification) and purified in this stage.

2-Methyl-5-fluoro-3-nitrobenzoic acid methyl ester

8.56 g (42.99 mmol) of 2-methyl-5-fluoro-3-nitrobenzoic acid is added in76 ml of N,N-dimethylformamide and mixed with 9.15 g (64.48 mmol) ofmethyl iodide and 8.91 g (64.48 mmol) of potassium carbonate. After 65hours of stirring at room temperature, the reaction mixture is added toice water and extracted several times with ethyl acetate. The combinedorganic extracts are washed with water and brine. After drying (sodiumsulfate), desiccant is suctioned out, and the solvent is spun off.Repeated chromatography on silica gel (mobile solvent ethylacetate/hexane) yields the desired compound, specifically in a yield of25.9% (2.37 g).

¹H-NMR (300 MHz, CDCl₃): δ=2.60 (3H), 3.96 (3H), 7.61 (1H), 7.77 (1H).

2-(Bromomethyl)-5-fluoro-3-nitrobenzoic acid methyl ester

2.37 g (11.12 mmol) of 5-fluoro-2-methyl-3-nitrobenzoic acid methylester is added in 35 ml of carbon tetrachloride and mixed with 2.24 g(12.24 mmol) of N-bromosuccinimide and 5.4 mg of benzoyl peroxide. Afterfour days of refluxing, the succinimide is suctioned off (glass-fiberfilter) after cooling, and then the filtrate is spun in until a drystate is reached. Chromatography on a Flashmaster yields 2.47 g (75.9%)of the desired compound.

¹H-NMR (300 MHz, CDCl₃): δ=4.01 (3H), 5.13 (2H), 7.72 (1H), 7.87 (1H).

2-(Azidomethyl)-5-fluoro-3-nitrobenzoic acid methyl ester

2.47 g (8.46 mmol) of 2-(bromomethyl)-5-fluoro-3-nitrobenzoic acidmethyl ester is mixed with 8.3 ml of N,N-dimethylformamide and 5.5 ml ofwater. After 0.82 g (12.66 mmol) of sodium azide is added, the batch isstirred overnight. The reaction mixture is added to water and extractedthree times with methyl tert-butyl ether. The combined organic extractsare washed with water and with brine. After drying on sodium sulfate, itis filtered, and the solvent is spun off. Chromatography on aFlashmaster yields 2.06 g (95.8%) of the desired azide.

¹H-NMR (300 MHz, CDCl₃): δ=4.00 (3H), 4.90 (2H), 7.73 (1H), 7.87 (1H).

4-Amino-6-fluoro-2,3-dihydroisoindol-1-one

1.86 g (7.32 mmol) of 2-(azidomethyl)-5-fluoro-3-nitrobenzoic acidmethyl ester is added in 46 ml of ethanol and 3.4 ml of glacial aceticacid and mixed with 256.6 mg of Pd/C. After stirring overnight at roomtemperature under hydrogen atmosphere, the catalyst is suctioned off viaa glass-fiber filter, and the filtrate is evaporated to the dry state.The residue, 1.18 mg (97.5%) of the desired compound, is furtherincorporated in crude form.

¹H-NMR (300 MHz, DMSO-d₆): δ=4.10 (2H), 5.75 (2H), 6.46-6.57 (2H), 8.50(1H).

4-{[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidene]amino}6-fluoro-2,3-dihydroisoindol-1-one

400 mg (1.297 mmol) ofrac-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanalis stirred with 215.5 mg (1.297 mmol) of4-amino-6-fluoro-2,3-dihydroisoindol-1-one in 1.89 ml of glacial aceticacid for four days at room temperature. Since starting material is stillpresent according to TLC, the reaction mixture is mixed with toluene andboiled in a water separator for 20 hours. The mixture is mixed threetimes with toluene and evaporated to the dry state in a rotaryevaporator. The residue is chromatographed on silica gel (mobile solventethyl acetate/hexane). 383.4 mg (64.7%) of the desired compound isisolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.37 (3H), 1.53 (3H), 2.20 (1H), 3.47 (1H),3.88 (3H), 4.32 (2H), 4.57 (1H), 6.22 (1H), 6.63-6.88 (4H), 7.42 (1H),7.48 (1H).

4-{[8-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-fluoro-2,3-dihydroisoindol-1-one

380 mg (0.832 mmol) of4-{[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}6-fluoro-2,3-dihydroisoindol-1-oneis mixed at room temperature with 8.3 ml of a 1 M solution of BBr₃ indichloromethane and stirred for one hour at ice bath temperature. Theworking-up of the batch is carried out as described in Example 4. Afterchromatography of the crude product on a Flashmaster (amine phase;mobile solvent methanol/dichloromethane), 9.2 mg (2.7%) of the desiredcompound is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.53 (3H), 1.69 (3H), 2.02 (1H), 2.22 (1H),4.28 (2H), 5.09 (1H), 6.60-7.00 (4H).

Example 54-{[5-Fluoro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one2-Fluoro-3-methoxybenzaldehyde

27 ml (240.62 mmol) of 2-fluoroanisole is dissolved in 700 ml oftetrahydrofuran. At −70° C., 200 ml of sec-BuLi (1.3 M solution incyclohexane) is added in drops. It is stirred for one hour at −70° C.,and then 152 ml of N,N-dimethylformamide, dissolved in 50 ml oftetrahydrofuran, is added in drops at this temperature. After anotherhour of stirring at −70° C., 380 ml of hydrochloric acid (w=10%) isadded in drops. In this case, the batch slowly comes to roomtemperature. After stirring overnight at room temperature, methyltert-butyl ether is added, and the organic phase is separated aftervigorous stirring. The aqueous phase is extracted two more times withmethyl tert-butyl ether. The combined organic extracts are washed withbrine and dried. After the desiccant is filtered off, the solvent isspun off, and the residue is chromatographed on silica gel (mobilesolvent ethyl acetate/hexane). 25.66 g (69.2%) of the desired compoundis isolated.

¹H-NMR (300 MHz, CDCl₃): δ=3.95 (3H), 7.13-7.26 (2H), 7.38-7.45 (1H),10.4 (1H).

2-Fluoro-3-methoxybenzyl alcohol

25.66 g (166.47 mmol) of 2-fluoro-3-methoxybenzaldehyde is dissolved in140 ml of ethanol and mixed in portions at 0° C. with 3.15 g (83.35mmol) of sodium borohydride. After one hour of stirring at roomtemperature, the reaction mixture is mixed with water and extractedthree times with methyl tert-butyl ether. The combined organic extractsare shaken with water and brine, dried, the desiccant is suctioned off,and the solvent is spun off. The remaining residue is chromatographed onsilica gel (mobile solvent ethyl acetate/hexane). 24.79 g (95.3%) of thedesired compound is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=3.90 (3H), 4.78 (2H), 6.87-7.10 (3H).

2-Fluoro-3-methoxybenzyl chloride

24.79 g (158.75 mmol) of 2-fluoro-3-methoxybenzyl alcohol is dissolvedin 35 ml of dichloromethane. While being cooled slightly, 58.4 ml ofthionyl chloride is added in drops, and the batch is then stirredovernight at room temperature. The reaction mixture is spun in until adry state is reached, the residue is dissolved in methyl tert-butylether, and it is shaken twice with semi-saturated potassium carbonatesolution. The aqueous phase is extracted once with methyl tert-butylether. The combined organic extracts are worked up as usual. The residuethat is obtained is incorporated in crude form into the next stage.

¹H-NMR (300 MHz, CDCl₃): δ=3.90 (3H), 4.65 (2H), 6.90-7.10 (3H).

2-Fluoro-3-methoxybenzyl cyanide

24.89 g (142.56 mmol) of 2-fluoro-3-methoxybenzyl chloride is stirred in200 ml of DMSO with 8.38 g (171.07 mmol) of sodium cyanide for threehours at 90° C. The reaction mixture is poured into water and extractedfour times with methyl tert-butyl ether. The combined organic phases arewashed with brine, dried, the desiccant is suctioned off, and thesolvent is spun off. First, only a portion of the residue (21.43 g) isincorporated in crude form into the next stage.

¹H-NMR (300 MHz, CDCl₃): δ=3.77 (2H), 3.90 (3H), 6.89-7.07 (2H),7.08-7.15 (1H).

2-(2-Fluoro-3-methoxyphenyl)-2-methylpropanenitrile

4 g (24.22 mmol) of 2-fluoro-3-methoxybenzyl cyanide is dissolved in 38ml of N,N-dimethylformamide and mixed with 6.87 g (48.35 mmol) of methyliodide. At 0° C., 2.11 g (48.35 mmol) of sodium hydride (55%) is addedin portions within 45 minutes. After 20 hours of stirring at roomtemperature, the batch is poured into ice water and extracted threetimes with 200 ml each of diethyl ether. The organic phases are washedwith water and brine and dried. After the desiccant is filtered off andafter the solvent is spun off, the residue is chromatographed on silicagel (mobile solvent ethyl acetate/hexane). 4.66 g (99.5%) of the desiredcompound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.80 (6H), 3.90 (3H), 92-7.02 (1H), 7.02-7.11(2H).

2-(2-Fluoro-3-methoxyphenyl)-2-methylpropanal

4.66 g (24.12 mmol) of2-(2-fluoro-3-methoxyphenyl)-2-methylpropanenitrile is dissolved in 96ml of toluene. At −65° C. to −60° C., 30 ml (36.18 mmol) of a 1.2 molarsolution of DIBAH in toluene is added in drops. After three and one-halfhours of stirring at −65° C., 276 ml of a 10% L(+)-tartaric acidsolution is added in drops at this temperature. In this case, thetemperature rises to 0° C. The cold bath is removed, and the batch isstirred vigorously at room temperature for one hour. The reactionmixture is extracted three times with 300 ml each of diethyl ether. Thecombined organic extracts are treated as usual (water, brine, drying).After the solvent is spun off, 4.78 g (slightly above 100%) of thedesired compound remains.

¹H-NMR (300 MHz, CDCl₃): δ=1.46 (6H), 3.89 (3H), 6.85-6.7.00 (2H),7.08-7.15 (1H), 9.65 (1H).

E/Z-4-(2-Fluoro-3-methoxyphenyl)-4-methylpent-2-enoic acid methyl ester

20.26 g (111.26 mmol) of phosphonoacetic acid trimethyl ester isintroduced into 68 ml of tetrahydrofuran. At 0° C., 61 ml of a 2 Msolution of LDA in THF/heptane/ethylbenzene is added in drops. After 45minutes of stirring, 21.83 g (111.26 mmol) of2-(2-fluoro-3-methoxyphenyl)-2-methylpropanal, dissolved in 68 ml oftetrahydrofuran, is added in drops at 0° C. After stirring overnight,the reaction mixture is mixed with water while being cooled in an icebath, and it is extracted three times with methyl tert-butyl ether. Thecombined organic extracts are treated as usual, and the residue that isobtained is chromatographed on silica gel (mobile solvent ethylacetate/hexane). 23.30 g (75.8%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.50 (6H), 3.73 (3H), 3.88 (3H), 5.74 (1H),5.80 (1H), 6.80-7.10 (3H).

4-(2-Fluoro-3-methoxyphenyl)-4-methylpentanoic acid methyl ester

23.30 g (84.33 mmol) ofE/Z-4-(2-fluoro-3-methoxyphenyl)-4-methylpent-2-enoic acid methyl esteris mixed in 310 ml of ethanol with 1.2 g of palladium on carbon, and itis stirred under hydrogen atmosphere overnight at room temperature. Thecatalyst is removed by filtration through a glass-fiber filter, and theresidue that remains after concentration by evaporation ischromatographed on silica gel (mobile solvent ethyl acetate/hexane).19.58 g (83.4%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.48 (6H), 2.00-2.18 (4H), 3.60 (3H), 3.90(3H), 6.78-7.03 (3H).

4-(2-Fluoro-3-methoxyphenyl)-2-hydroxy-4-methylpentanoic acid methylester

19.58 g (77 mmol) of 4-(2-fluoro-3-methoxyphenyl)-4-methylpentanoic acidmethyl ester is introduced into 245 ml of tetrahydrofuran, and thereaction mixture is cooled to −70° C. Within one hour, 220.7 ml of a 0.5molar solution of potassium-bis-(trimethylsilylamide) in toluene isadded in drops, and the reaction mixture is then stirred for 45 moreminutes at −70° C. 28.3 g (107.79 mmol) of Davis reagent, dissolved in245 ml of tetrahydrofuran, is now added in drops within 40 minutes.After two hours of stirring at −70° C., 250 ml of saturated ammoniumchloride solution is slowly added in drops, and in this case, the batchis brought to room temperature. After extraction with methyl tert-butylether, the combined organic extracts are treated as usual with water andbrine. After the solvent is spun off, the residue is chromatographedseveral times on silica gel (mobile solvent ethyl acetate/hexane). 12.14g (58.3%) of the desired compound is ultimately isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.45 (3H), 1.49 (3H), 1.90-2.01 (1H),2.38-2.50 (2H), 3.70 (3H), 3.90 (3H), 3.92-4.03 (1H), 6.80-7.08 (3H).

Methyl-4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-oxopentananoate

11.14 g (41.22 mmol) of methyl4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-pentanoate is added in260 ml of dichloromethane and 71.3 ml of dimethyl sulfoxide. After 20.8g (205.78 mmol) of triethylamine is added, the batch is mixed with 13 g(81.71) of SO₃/pyridine complex and then stirred overnight at roomtemperature. The reaction mixture is mixed with 100 ml of saturatedammonium chloride solution while being cooled slightly, and it isstirred vigorously. After 3× extraction with methyl tert-butyl ether,the combined organic phases are treated as usual. The residue thatremains after the solvent is spun off is chromatographed together withthe residue, which results from a sample batch (1 g), on silica gel(mobile solvent ethyl acetate/hexane). 10.03 g (83.2%, from bothbatches) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.49 (6H), 3.39 (2H), 3.73 (3H), 3.89 (3H),6.80-6.91 (2H), 6.95-7.07 (1H).

Methyl-4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoate

10.03 g (37.39 mmol) ofmethyl-4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-oxopentanoate isdissolved in 63 ml of tetrahydrofuran, mixed with 5.68 g (39.98 mmol) of(trifluoromethyl)-trimethylsilane and then with 82.3 mg oftetrabutylammonium fluoride. After stirring overnight at roomtemperature, the batch is added to ice water, extracted with methyltert-butyl ether, and the combined organic extracts are treated asusual. After the solvent is spun off, the residue is chromatographed onsilica gel (mobile solvent ethyl acetate/hexane). In addition to 6.94 g(45.2%) of the desired product, 2.75 g of starting material(COntaminated) is isolated, which is again subjected to the sameprocedure. As a result, another 1.91 g ofmethyl-4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoateis included.

MS (CI): 428 (100%), 395 (67%).

4-(2-Fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)pentan-1-oland4-(2-Fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-1-(trimethylsilyloxy)pentan-2-ol

8.85 g (21.56 mmol) ofmethyl-4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoateis dissolved in 77 ml of diethyl ether. 1.64 g (43.12 mmol) of lithiumaluminum hydride is added to this solution in portions at 0° C. Afterfour hours of stirring at room temperature, it is cooled again to 0° C.and about 80 ml of saturated sodium bicarbonate solution is carefullyadded in drops. Then, it is vigorously stirred at room temperature forone hour. The batch is extracted several times with methyl tert-butylether. The combined organic extracts are washed with water and then withbrine. After drying on sodium sulfate, the desiccant is suctioned off,the solvent is spun in, and the residue (7.36 g; mixture of the tworegioisomeric silyl ethers) is incorporated in crude form into the nextstage.

4-(2-Fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol

7.36 g (19.24 mmol) of the mixture of the two silyl ethers is dissolvedin 108 ml of tetrahydrofuran, mixed with 6.07 g (19.24 mmol) oftetrabutylammonium fluoride-trihydrate and stirred overnight at roomtemperature. The reaction mixture is diluted with methyl tert-butylether, washed with water and brine, and then the organic solvent is spunoff after drying. After chromatography on silica gel (mobile solventethyl acetate/hexane), 5.3 g (88.8%) of the desired compound isobtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.45 (3H), 1.58 (3H), 2.20 (1H), 2.38 (2H),2.93 (1H), 3.30-3.40 (1H), 3.50-3.60 (1H), 3.89 (3H), 6.85-6.98 (2H),6.98-7.09 (1H).

4-(2-Fluoro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal

2.5 g (8.06 mmol) ofrac-4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diolis introduced into a mixture that consists of 52 ml of dichloromethane,14 ml of dimethyl sulfoxide and 4.08 g (40.29 mmol) of triethylamine. Atroom temperature, 2.57 g (16.11 mmol) of SO₃/pyridine complex is added,and the batch is stirred overnight at this temperature. The reactionmixture is mixed with saturated ammonium chloride solution and stirredvigorously. After additional common working-up, 2.11 g (85%) of thedesired aldehyde is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.45 (3H), 1.50 (3H), 2.30 (1H), 3.12 (1H),3.62 (1H), 3.89 (3H), 6.75 (1H), 6.90 (1H), 7.00 (1H), 9.15 (1H).

4-{[5-Fluoro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one

150 mg (0.487 mmol) of4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-trifluoromethyl-pentanal ismixed in 0.9 ml of glacial acetic acid with 72.7 mg (0.487 mmol) of4-amino-2,3-dihydroisoindol-1-one, and it is stirred for two days atroom temperature. The batch is spun in until a dry state is reached, andthe residue is chromatographed (Flashmaster). 119.8 mg (56.2%) of thedesired cyclic compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.50 (3H), 1.65 (3H), 2.05 (1H), 2.20 (1H),3.83 (3H), 4.29 (2H), 4.40 (1H), 5.00 (1H), 6.79 (1H), 6.93 (1H),7.00-7.12 (2H), 7.21 (1H), 7.35 (1H).

4-{[5-Fluoro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-Z3-dihydroisoindol-1-one

109.8 mg (0.250 mmol) of (rac.)4-{[5-fluoro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-oneis mixed with 3.4 ml of a 1 M solution of BBr₃ in dichloromethane andstirred for four hours at room temperature. The batch is mixed at 0° C.with saturated sodium bicarbonate solution and extracted twice withethyl acetate. The combined organic extracts are dried on sodiumsulfate. After the desiccant is filtered off, and after the solvent isspun off, the residue is chromatographed on a Flashmaster. 15.6 mg(14.7%) of the final product is isolated.

¹H-NMR (300 MHz, CD₃OD): δ=1.53 (3H), 1.67 (3H), 2.03-2.20 (2H),4.28-4.43 (2H), 5.13 (1H), 6.78 (1H), 6.90 (2H), 7.18 (1H), 7.38 (1H).

Example 64-{[7-Bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-1,3-dihydroindol-2-one4-Amino-1,3-dihydroindol-2-one Dimethyl-2-(2,6-dinitrophenyl)-malonate

42.95 g (311.03 mmol) of dimethyl malonate is dissolved in 300 ml ofN,N-dimethylformamide and mixed in portions with 35.15 g (296.22 mmol)of potassium-tert. butylate. After the tert-butanol that was producedhas been distilled off, the reaction mixture is cooled to 20° C. 30 g(148.11 mmol) of 2,6-dichlorobenzene is quickly added in portions to themixture. After three hours of stirring at 90° C., it is stirredovernight at room temperature. The reaction mixture is added to 800 mlof 1% NaOH solution (ice-cooled) and extracted three times with methyltert-butyl ether. The combined ether phases are discarded according toTLC monitoring. The aqueous phase is carefully acidified withconcentrated nitric acid (w=65%) while being cooled in an ice bath. 6×extraction with methyl tert-butyl ether, common working-up of thecombined organic extracts (water, brine, drying, filtering andspinning-off of solvent) yields a residue that is chromatographed onsilica gel (mobile solvent ethyl acetate/hexane). 12.09 g (27.09%) ofthe desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=3.82 (6H), 5.39 (1H), 7.75 (1H), 8.27 (2H).

Methyl-(2,6-Dinitrophenyl)-acetate

10.08 g (33.8 mmol) of dimethyl-2-(2,6-dinitrophenyl)-malonate is mixedin 54 ml of glacial acetic acid with 2.7 ml of perchloric acid andrefluxed at 125° C. In this case, the ethyl acetate that is produced isdistilled off. After 90 minutes, the reaction is brought to a halt,since starting material is no longer present according to TLC. Thereaction mixture is poured into ice water and extracted three times withethyl acetate. The combined organic extracts are shaken with 5% sodiumbicarbonate solution, with water and with brine. After the organic phaseis dried, the desiccant is filtered off and the solvent is spun off, aresidue remains that is chromatographed on silica gel (mobile solventethyl acetate/hexane). 4.69 g of the (2,6-dinitrophenyl)-acetic acid,which then is esterified with methanol (16 ml) and concentrated sulfuricacid (0.4 ml), is isolated. To this end, the acid and the reagents arerefluxed for seven hours. The methanol is spun off, and the residue isworked up in the usual way. After chromatography on silica gel (mobilesolvent ethyl acetate/hexane), 4.43 g (89%) of the desired ester isobtained.

¹H-NMR (300 MHz, CDCl₃): δ=3.75 (3H), 4.20 (2H), 7.69 (1H), 8.19 (2H).

4-Amino-1,3-dihydroindol-2-one

4.43 g (18.45 mmol) of methyl-(2,6-dinitrophenyl)-acetate is added in38.8 ml of glacial acetic acid and 11 ml of water and mixed with 3.75 gof iron powder and stirred for four more hours. In this case, heating to40 to 60° C. takes place. The reaction mixture is added to ice water,mixed with ethyl acetate and vigorously stirred for ten minutes. Themixture is filtered through a glass-fiber filter, the organic phase isseparated, and the aqueous phase is extracted twice more with ethylacetate. The combined organic extracts are washed with brine, dried, andthe solvent is spun off after the desiccant is filtered off. The residueis chromatographed on silica gel (mobile solventmethanol/dichloromethane). 2.38 g of 4-nitro-indol-2-one is isolated.The nitro compound is mixed again in glacial acetic acid/water with 2.7g of iron powder, and the above-described cycle is passed throughanother time. 1.63 g of the desired amine is isolated.

¹H-NMR (300 MHz, DMSO-d₆): δ=3.19 (2H), 5.03 (2H), 6.08 (1H), 6.22 (1H),6.85 (1H), 10.10 (1H).

4-(4-Bromo-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol

2.55 g (6.17 mmol) of4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanoicacid ethyl ester (synthesized in two stages starting from4-(4-bromo-2-methoxyphenyl)-2-oxopentanoic acid, WO 98/54159) isdissolved in 102 ml of diethyl ether, mixed in portions at 0 to −5° C.with 351.3 mg (9.256 mmol) of lithium aluminum hydride and stirred forthree and one-half hours at room temperature. The reaction mixture ismixed drop by drop with saturated sodium bicarbonate solution whilebeing cooled in an ice bath and stirred for 15 minutes at 5° C. and thenfor one hour at room temperature. The deposited precipitate is suctionedoff, rewashed with diethyl ether, and the filtrate is concentrated byevaporation in a rotary evaporator. The residue is chromatographed onsilica gel (mobile solvent ethyl acetate/hexane). In addition to 308 mgof the aldehyde (see next stage), 2.025 g (88.4%) of the diol isobtained.

4-(4-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal

2.03 g (5.442 mmol) of4-(4-bromo-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diolis oxidized to aldehyde according to Swern as described in Example 3.1.839 g (91.4%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.39 (3H), 1.45 (3H), 2.23 (1H), 3.35 (1H),3.58 (1H), 3.90 (3H), 6.93-7.09 (3H), 9.03 (1H).

4-{[4-(4-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidene]amino}-1,3-dihydroindol-2-one

300 mg (0.812 mmol) of4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanalis stirred in 1.5 ml of glacial acetic acid with 120.4 mg (0.812 mmol)of 4-amino-1,3-dihydroindol-2-one over a weekend at room temperature.The reaction mixture is evaporated until a dry state is reached, and theresidue is put on a Flashmaster column. 235.9 mg (58.1%) of the desiredimine is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.35 (3H), 1.53 (3H), 2.20 (1H), 3.30 (1H),3.42 (2H), 3.85 (3H), 4.71 (1H), 6.05 (1H), 6.78 (1H), 6.80-6.90 (2H),6.98 (1H), 7.19 (1H), 7.45 (1H), 8.25 (1H).

4-{[7-Bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino}-],3-dihydroindol-2-one

235.9 mg of4-{[4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}-1,3-dihydroindol-2-oneis mixed at 0° C. with 6.42 ml of a 1 M solution of BBr₃ indichloromethane and stirred for four hours at room temperature. At 0°C., saturated sodium bicarbonate solution is carefully added in drops.After 3× extraction with ethyl acetate, the organic phases are dried onsodium sulfate. The desiccant is suctioned off, and the solvent is spunoff. The residue is chromatographed on a Flashmaster. 125.4 mg (54%) ofthe desired compound is isolated.

¹H-NMR (300 MHz, CD₃OD): δ=1.52 (3H), 1.65 (3H), 1.98-2.18 (2H),3.25-3.49 (2H), 4.98 (1H), 6.37 (1H), 6.47 (1H), 6.87 (1H), 7.02 (1H),7.11 (1H).

Example 7(+)-4-({7-Hydroxy-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydronaphtho[1,2-d]-1,3-dioxol-6-yl}amino)-2,3-dihydroisoindol-1-oneand(−)-4-({7-Hydroxy-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydronaphtho[1,2-d]-1,3-dioxol-6-yl}amino)-2,3-dihydroisoindol-1-one1,3-Benzodioxole-4-carboxylic acid-methyl ester

50 g of 2,3-dihydroxybenzoic acid in 450 ml of methanol is mixed drop bydrop with 50 ml of thionyl chloride at room temperature. Then, thesolution is heated for five hours to 60° C. and still stirred overnightat room temperature. The solvent is completely removed in a vacuum, andthe remaining oil is taken up in diethyl ether and extracted withsaturated sodium bicarbonate solution. After washing with brine, dryingwith sodium sulfate and removal of the solvent in a vacuum, 46 g of2,3-dihydroxybenzoic acid-methyl ester is obtained. The latter is mixedin 575 ml of DMF and 20.2 ml of dibromomethane with 56.7 g of potassiumcarbonate, and it is heated for five hours under argon to 100° C. Then,it is stirred overnight at room temperature. After mixing with water, itis extracted three times with ethyl acetate. The organic phase is washedseveral times with water and dried on sodium sulfate. The solvent isremoved in a vacuum, and 50.2 g of 1,3-benzodioxole-4-carboxylicacid-methyl ester is obtained as a brown solid.

Melting point: 55-57° C.

4-(1,3-Benzodioxol-4-yl)-4-methyl-2-oxopentanoic acid ethyl ester

4.76 g of 1,3-benzodioxole-4-carboxylic acid-methyl ester in 65 ml ofdry THF is added in drops at room temperature to a solution of 21 ml of3 M methylmagnesium chloride in THF under argon. The reaction mixture isstirred for three hours and then slowly mixed with 1N hydrochloric acid.After extraction with ethyl acetate and after the organic phase iswashed with water, it is dried with sodium sulfate, and the solvent isremoved in a vacuum. 5 g of 1-(1,3-benzodioxol-4-yl)-1-methylethanol isobtained as a brown oil. The tertiary alcohol (27.17 mmol) is mixedtogether with 7.8 g (41.6 mmol) of 2-(trimethylsilyloxy)-acrylic acidethyl ester in 100 ml of dichloromethane at −70° C. with 5.4 g (20.8mmol) of tin tetrachloride. After 15 minutes of stirring at −70° C., thesolution is poured onto semi-saturated sodium carbonate solution, mixedwith ethyl acetate and stirred vigorously. The phases are separated, andthe aqueous phase is extracted twice with ethyl acetate. The organicphase is washed with brine, dried with sodium sulfate, and the solventis removed in a vacuum. 7.15 g of a yellow oil that is distilledtogether with the products from several batches of a similar order ofmagnitude is obtained.

4-(1,3-Benzodioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanoicacid ethyl ester

6.1 g (21.91 mmol) of 4-(1,3-benzodioxol-4-yl)-4-methyl-2-oxopentanoicacid ethyl ester, dissolved in 130 ml of tetrahydrofuran, is reactedwith 9.5 ml (65.7 mmol) of (trifluoromethyl)trimethylsilane and 4.42 mlof a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran.Carrying out and working up the reaction are carried out as described inExample 3. The crude product that is obtained is purified together withone batch of a similar order of magnitude [9.19 g (33.02 mmol) of4-(1,3-benzodioxol-4-yl)-4-methyl-2-oxopentanoic acid ethyl ester as astarting material] by chromatography on silica gel (mobile solvent ethylacetate/hexane). 16.45 g (86%) of the desired product is isolated fromthe two batches.

4-(1,3-Benzodioxol-4-yl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol

12.5 g (36.03 mmol) of4-(1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanoicacid ethyl ester is introduced into 430 ml of diethyl ether and mixed inportions with 2.05 g (54.1 mmol) of lithium aluminum hydride at 0° C.After stirring overnight at room temperature, the batch is carefullyadded to sodium bicarbonate solution. It is filtered by means ofdiatomaceous earth and extracted three times with ethyl acetate. Thecombined organic extracts are washed with brine, dried, and the solventis spun off after the desiccant is filtered off. Chromatography of theresidue on silica gel (mobile solvent ethyl acetate/hexane) yields 6.7 g(61%) of the desired alcohol.

4-(1,3-Benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal

2.26 g (7.38 mmol) of4-(1,3-benzodioxol-4-yl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol isoxidized to aldehyde as described in Example 3 according to Swern. Afterthe conventional working-up, the residue is chromatographed on aFlashmaster. 1.85 g (82.3%) of the desired aldehyde is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.39 (3H), 1.48 (3H), 2.27 (1H), 3.10 (1H),3.67 (1H), 5.92-6.02 (2H), 6.60-6.70 (1H), 6.70-6.88 (2H), 9.06 (1H).

(+)-4-({7-Hydroxy-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydronaphtho[1,2-d]-1,3-dioxol-6-yl}amino)-2,3-dihydroisoindol-1-oneand(−)-4-({7-Hydroxy-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydronaphtho[1,2-d]-1,3-dioxol-6-yl}amino)-2,3-dihydroisoindol-1-one

800 mg (2.63 mmol) of4-(1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanalis stirred in 5.2 ml of glacial acetic acid with 389 mg (2.63 mmol) of4-amino-2,3-dihydroisoindol-1-one overnight at room temperature. Thereaction mixture is spun in until a dry state is reached, and theresidue is chromatographed on a Flashmaster. 725 mg (62.8%) of thedesired compound is isolated as a racemate. Racemate cleavage (ChiralpakAD 20μ; mobile solvent: hexane/ethanol/diethylamine) yields 279.2 mg ofthe (+)-enantiomer {[α]_(D)=+20.7 (c=1.03, methanol)} and 297.5 mg ofthe (−)-enantiomer {[α]_(D)=−23.4 (c=1.02, methanol)}

Example 85-{[8-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one4-(5-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal

2 g (6.12 mmol) of4-(5-chloro-2-methoxyphenyl)-hydroxy-4-methyl-2-trifluoromethyl-pentan-1-olis oxidized with 854.6 mg (6.733 mmol) of oxalyl chloride and 1.05 ml(14.812 mmol) of DMSO as described in Example 2 according to Swern.After the working-up, 1.95 g (98.4%) of the desired aldehyde isobtained, which is incorporated in crude form into the next stage.

¹H-NMR (300 MHz, CDCl₃): δ=1.39 (3H), 1.49 (3H), 2.27 (1H), 3.32 (1H),3.59 (1H), 3.88 (3H), 6.78 (1H), 7.10 (1H), 7.20 (1H), 9.09 (1H).

5-{[4-(5-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentylidene]amino}isoquinolin-1(2H)-one

300 mg (0.924 mmol) of4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanalis stirred with 148 mg (0.924 mmol) of 5-amino-isoquinolin-1-one in 1.33ml of glacial acetic acid for four days at room temperature. The mixtureis drawn off three times with toluene and evaporated in a rotaryevaporator until a dry state is reached. The residue is chromatographedon silica gel (mobile solvent ethyl acetate/hexane). 345.8 mg (80.1%) ofthe desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.39 (3H), 1.57 (3H), 2.29 (1H), 3.49 (1H),3.83 (3H), 4.82 (1H), 6.57-6.65 (2H), 6.72 (1H), 6.89 (1H), 7.03 (1H),7.18-7.29 (1H), 7.36 (1H), 7.40 (1H), 8.32 (1H), 10.98 (1H).

5-{[8-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one

50 mg (0.107 mmol) of the compound5-{[4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}2,3-isoquinolin-1-onethat is described in the paragraph above is mixed at −20° C. with 2.1 mlof a 1 M solution of boron tribromide in dichloromethane, and it isstirred for two and one-half hours in a temperature range of between−20° C. and 0° C. The reaction mixture is mixed drop by drop at −20° C.with saturated sodium bicarbonate solution. After dilution with ethylacetate, the cold bath is removed, and the batch is stirred for 15minutes at room temperature. It is extracted twice with 30 ml each ofethyl acetate. The combined organic extracts are washed with water andsaturated NaCl solution. After being dried on sodium sulfate, thesolvent is spun off, and the remaining residue is chromatographed onsilica gel (mobile solvent ethyl acetate/hexane). 16.5 mg (33%) of thedesired compound is isolated.

MS (ES+): 453, 455

Example 98-Bromo-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol)4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoicacid ethyl ester

34.45 g (258.91 mmol) of aluminum trichloride is introduced into 354.35g (237.02 mmol) of 4-bromoanisole. 38.95 g (172.19 mmol) of2-hydroxy-4-methylene-2-(trifluoromethyl)pentanoic acid ethyl ester isadded in drops to this mixture within one hour. After stirring overnightat room temperature, the batch is added to ice water and made acidicwith 10% hydrochloric acid. After 3× extraction with ethyl acetate, thecombined organic extracts are washed with 1N hydrochloric acid andbrine. After drying on magnesium sulfate, the solvent is spun off. Mostof the excess 4-bromoanisole is distilled off (10 mbar; bath temperature110° C.). After chromatography on silica gel (mobile solvent ethylacetate/hexane), 36.87 g (51.8%) of the desired compound is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.39 (3H), 1.46 (3H), 2.49 (1H), 2.85 (1H),3.48 (1H), 3.62-3.75 (1H), 3.85 (3H), 4.02-4.15 (1H), 6.73 (1H),7.23-7.33 (2H).

4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol

3 g (7.25 mmol) of4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoicacid ethyl ester is dissolved in 120 ml of diethyl ether, and thereaction mixture is cooled to 0° C. 426.5 mg (10.89 mmol) of lithiumaluminum hydride is added in portions. After two hours of stirring atroom temperature, starting material is no longer present. The batch ismixed with saturated sodium bicarbonate solution while being cooled inan ice bath, the precipitate is suctioned off, and it is washed withdiethyl ether. After spinning-in, the residue is chromatographed on aFlashmaster. In addition to 540.5 mg of4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal,1.14 g of the desired alcohol (which, however, also contains the Desbromcompound) is isolated.

4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal

1.13 g (3.06 mmol) of4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-olis added in 20 ml of dichloromethane and 5.4 ml of DMSO. After mixingwith 1.55 g (15.32 mmol) of triethylamine and 975.28 mg (6.13 mmol) ofSO₃/pyridine complex, the batch is stirred overnight at roomtemperature. After TLC, another spatula tip full of SO₃/pyridine complexis added, and it is further stirred for several hours. The reactionmixture is mixed with saturated ammonium chloride solution and shakenout three times with methyl tert-butyl ether. The combined organicextracts are washed with water and brine. After the solvent is dried andspun off, the residue is chromatographed on a Flashmaster. 902.7 mg(79.81%) of the desired aldehyde (together with the Desbrom compound) isisolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (3H), 1.50 (3H), 2.28 (1H), 3.30 (1H),3.87 (3H), 6.73 (1H), 7.22 (1H), 7.35 (1H), 9.09 (1H).

1,1,1-Trifluoro-4-(5-bromo-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol

300 mg (0.813 mmol) of4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanalis mixed in 1.19 ml of glacial acetic acid with 108.2 mg (0.813 mmol) of4-aminoindazole, and it is stirred for four days at room temperature.The batch is spun in until a dry state is reached, and the residue isdrawn off three times with toluene. Chromatography on silica gel (mobilesolvent ethyl acetate/hexane) yields 352.5 mg (89.5%) of the desiredimine (together with the imine of the Desbrom compound).

¹H-NMR (300 MHz, CDCl₃): δ=1.48 (3H), 1.55 (3H), 2.28 (1H), 3.44 (1H),3.80 (3H), 4.98 (1H), 6.35 (1H), 6.53 (1H), 6.99 (1H), 7.30 (1H),7.29-7.40 (1H), 7.55 (1H), 7.99 (1H), 10.28 (1H).

8-Bromo-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

100 mg (0.206 mmol) of1,1,1-trifluoro-4-(5-bromo-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-olis dissolved in one milliliter of dichloromethane, and the reactionmixture is cooled to −30° C. Four milliliters of a 1 M solution of BBr₃in dichloromethane is added in drops within 15 minutes, and the batch isthen stirred for 45 more minutes at −30° C. At −30° C., about 10 ml of asaturated sodium bicarbonate solution is carefully added in drops. Afterdilution with ethyl acetate, it is stirred for ten minutes and thenextracted twice with 50 ml each of ethyl acetate. The combined organicextracts are washed with water and brine. The residue that is obtainedafter the solvent is dried and spun off is chromatographed several timeson silica gel (mobile solvent ethyl acetate/dichloromethane). 21 mg ofthe desired compound (together with the corresponding Desbrom compound)is isolated.

¹H-NMR (300 MHz, CD₃OD): δ=1.55 (3H), 1.67 (3H), 2.10 (1H), 2.43 (1H),3.89 (3H), 5.25 (1H), 6.72 (1H), 6.83 (1H), 6.90 (1H), 7.22 (1H), 7.49(1H), 8.25 (1H).

8-Bromo-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

21 mg (0.043 mmol) of8-bromo-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-olis mixed at room temperature with 0.4 ml of a 1 M BBr₃ solution andstirred for 19 hours at room temperature. After the reaction mixture ismixed with ice, saturated sodium bicarbonate solution is added drop bydrop, and it is diluted with ethyl acetate. The organic phases arewashed neutral as usual, and the residue that remains after the solventis spun in is chromatographed on silica gel (mobile solventmethanol/dichloromethane). 17.1 mg (83.8%) of the desired compound(together with the Desbrom compound) is isolated.

¹H-NMR (300 MHz, CD₃OD): δ=1.59 (3H), 1.71 (3H), 2.10 (1H), 2.42 (1H),5.25 (1H), 6.64-6.78 (2H), 6.83 (1H), 7.20-7.34 (2H), 8.25 (1H).

Example 101-[(1H-Indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol2-Hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal

10.4 g of 4-methyl-2-oxo-4-phenylpentanoic acid (WO98/54159) in 250 mlof dimethylformamide is mixed at −5° C. with 4.1 ml of thionyl chlorideand after 15 minutes, it is mixed with 4 ml of methanol. After 15 hoursat room temperature, the batch is diluted with water, and extracted withethyl acetate. The organic extracts are washed with water, dried(Na₂SO₄) and concentrated by evaporation, whereby 9.3 g of4-methyl-2-oxo-4-phenylpentanoic acid-methyl ester is obtained. Thelatter is mixed in 558 ml of DMF at −5° C. with 15.5 ml (104.63 mmol) of(trifluoromethyl)trimethylsilane and 20.5 g (63.28 mmol) of cesiumcarbonate, and it is stirred for 16 hours at room temperature. Water isadded, it is extracted with ethyl acetate, the organic phase is washedwith water and dried (Na₂SO₄). The intermediate product that isconcentrated by evaporation is taken up in 200 ml of THF, and 50 ml of a1 M solution of tetrabutylammonium fluoride in THF is added. It isstirred for 2 hours, water is added, it is extracted with ethyl acetate,the organic phase is washed with water and dried (Na₂SO₄). Afterchromatography on silica gel with hexane-ethyl acetate (0-30%), 8.35 gof 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanoic acid-methylester is obtained. The ester (8.3 g, 28.59 mmol) is dissolved in 180 mlof THF, and over a period of 2.5 hours, 1.52 g (36.20 mmol) of lithiumaluminum hydride is added in small portions. After complete conversion,5 ml of ethyl acetate is added in drops, and after another 10 minutes,10 ml of water is carefully added. Formed precipitate is filtered out,and it is washed carefully with ethyl acetate. After chromatography onsilica gel with hexane-ethyl acetate (0-35%), 5.40 g of4-methyl-4-phenyl-2-(trifluoromethyl)pentane-1,2-diol is obtained. 5.7ml (40.3 mmol) of triethylamine is added to 2.5 g (9.53 mmol) of diol in75 ml of dichloromethane and 28 ml of DMSO, and 5 g of pyridine/SO₃complex is added in portions over 20 minutes. It is stirred over 2hours, and 40 ml of saturated ammonium chloride solution is added. Themixture is stirred for another 15 minutes, the phases are separated, andit is extracted with dichloromethane. It is washed with water, and driedon sodium sulfate. The solvent is removed in a vacuum, and 3 g ofproduct is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.34 (s, 3H), 1.44 (s, 3H), 2.34 (d, 2H),2.66 (d, 1H), 3.64 (s, 1H), 7.03-7.41 (m, 4H), 8.90 (s, 1H).

1,1,1-Trifluoro-4-phenyl-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol

130 mg (0.50 mmol) of2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)-pentanal is dissolved in15 ml of toluene and mixed with 73 mg (0.55 mmol) of 4-amino-indazoleand with 0.22 ml of titanium tetraethylate and stirred at 100° C. for2.5 hours under argon. For working-up, the reaction solution is mixedwith 1 ml of saturated sodium chloride solution, and it is stirred for30 minutes. The suspension is then suctioned off over Celite and washedwith 200 ml of ethyl acetate. The organic phase is washed with saturatedsodium chloride solution, dried with sodium sulfate and concentrated byevaporation in a vacuum: 246 mg. Column chromatography on silica gelwith pentane-ethyl acetate yields 190 mg of the product.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.35 (s, 3H), 1.47 (s, 3H), 2.26 (d, 1H),2.73 (d, 1H), 6.13 (s, 1H), 6.24 (d, 1H), 6.94 (t, 1H), 7.06 (t, 2H),7.23 (t, 1H), 7.34-7.40 (m, 3H), 7.56 (s, 1H), 8.00 (s, 1H), 13.17 (s,1H).

1-[(1H-Indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

190 mg (0.51 mmol) of1,1,1-trifluoro-4-phenyl-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-olis dissolved in 100 ml of dichloromethane and cooled to −70° C. Thesolution is mixed over 10 minutes with 9 ml of titanium tetrachloridesolution (1 mol in dichloromethane), and it is stirred for 1 hour at−70° C. Then, the cold solution is poured into 200 ml of saturatedsodium bicarbonate solution and stirred for 15 minutes. For working-up,the mixture is extracted with dichloromethane, the organic phase iswashed with saturated sodium chloride solution, dried with sodiumsulfate and concentrated by evaporation in a vacuum: 208 mg. Columnchromatography with dichloromethane-methanol yields 53 mg (28%) of thedesired product.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.36 (s, 3H), 1.51 (s, 3H), 2.08 (d, 2H),5.35 (d, 1H), 5.93 (s, 1H), 6.24 (d, 1H), 6.32 (d, 1H), 6.74 (d, 1H),7.05-7.12 (m, 2H), 7.21-7.28 (m, 2H), 7.43 (d, 1H), 8.15 (s, 1H), 12.81(s, 1H).

Example 111-[(2-Methylbenzothiazol-7-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol1,1,1-Trifluoro-4-phenyl-2-[(2-methylbenzothiazolyl-7-yl)iminomethyl]-4-methylpentan-2-ol

¹H-NMR (300 MHz, DMSO-d₆): δ=1.33 (s, 3H), 1.47 (s, 3H), 2.24 (d, 1H),2.71 (d, 1H), 2.82 (s, 3H), 6.19, (s, 1H), 6.54 (d, 1H), 6.91 (t, 1H),7.02 (t, 2H), 7.31-7.40 (m, 3H), 7.51 (s, 1H), 7.78 (d, 1H).

1-[(2-Methylbenzothiazol-7-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, DMSO-d₆): δ=1.34 (s, 3H), 1.47 (s, 3H), 1.99-2.12 (m,2H), 2.78 (s, 3H), 5.38 (d, 1H), 5.68 (d, 1H), 6.10 (s, 1H), 6.78 (dd,1H), 7.07-7.16 (m, 2H), 7.20-7.28 (m, 3H), 7.41 (d, 1H).

Example 126-[(1H-Indazol-4-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1,3-dioxol-7-ol4-(1,3-Benzodioxol-4-yl)-1,1,1-trifluoro-2-[1H-indazoly-4-yl)iminomethyl]-4-methylpentan-2-ol

¹H-NMR (300 MHz, DMSO-d₆): δ=1.34 (s, 3H), 1.48 (s, 3H), 2.28 (d, 1H),2.93 (d, 1H), 5.90 (s, 2H), 6.15 (s, 1H), 6.29 (d, 1H), 6.45 (t, 1H),6.56 (dd, 1H), 6.62 (d, 1H), 7.23 (t, 1H), 7.40 (d, 1H), 7.74 (s, 1H),8.00 (s, 1H), 13.17 (s, 1H).

6-[(1H-Indazol-4-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1,3-dioxol-7-ol

¹H-NMR (300 MHz, DMSO-d₆): δ=1.43 (s, 3H), 1.55 (s, 3H), 2.04-2.12 (m,2H), 5.26 (d, 1H), 5.95 (s, 1H), 6.00 (s, 2H), 6.19 (d, 1H), 6.29 (d,1H), 6.70-6.78 (m, 3H), 7.07 (t, 1H), 8.12 (s, 1H), 12.81 (s, 1H).

Example 131-[(2-Methylquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol1,1,1-Trifluoro-4-phenyl-2-[(2-methylquinolin-5-yl)iminomethyl]-4-methylpentan-2-ol

120 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal, 67 mgof 5-amino-2-methylquinoline and 163 μl of titanium tetraethylate arestirred in 8 ml of toluene for 2 hours at 100° C. After cooling, thebatch is mixed with 2 ml of water, stirred for 15 minutes at roomtemperature, and concentrated by evaporation in a vacuum. Columnchromatography on silica gel with cyclohexane-ethyl acetate yields 111mg of product.

¹H-NMR (300 MHz, CDCl₃): δ=1.35 (s, 3H), 1.55 (s, 3H), 2.45 (d, 1H),2.75 (s, 3H), 2.80 (d, 1H), 5.00 (s, 1H), 6.15 (d, 1H), 6.9-7.1 (m, 3H),7.30 (m, 3H), 7.35 (d, 1H), 7.45 (t, 1H), 7.90 (d, 1H), 8.35 (d, 1H).

1-[(2-Methylquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

5.1 ml of a 1 M titanium tetrachloride-CH₂Cl₂ solution is added in dropsto a solution of 111 mg of1,1,1-trifluoro-4-phenyl-2-[(2-methylquinolin-5-yl)iminomethyl]-4-methylpentan-2-olin 84 ml of CH₂Cl₂ at −78° C. After 1 hour at −78° C., the batch ismixed with saturated NaHCO₃ and heated to room temperature. The phasesare separated, the aqueous phase is extracted with CH₂Cl₂, the combinedorganic phases are dried (Na₂SO₄) and concentrated by evaporation in avacuum. Column chromatography on silica gel with cyclohexane-ethylacetate yields 94 mg of product.

¹H-NMR (300 MHz, CDCl₃): δ=1.45 (s, 3H), 1.60 (s, 3H), 2.15 (d, 1H),2.20 (d, 1H), 2.75 (s, 3H), 3.05 (br., 1H), 4.85 (br. d, 1H), 5.20 (d,1H), 6.85 (d, 1H), 7.10 (t, 1H), 7.20 (d, 1H), 7.30 (t, 1H), 7.40 (d,1H), 7.50 (d, 1H), 7.55 (t, 1H), 8.05 (d, 1H).

Example 141-[(Quinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol1,1,1-Trifluoro-4-phenyl-2-[(quinolin-5-yl)iminomethyl]-4-methylpentan-2-ol

Analogously to Example 13, 120 mg of2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentanal and 61 mg of5-aminoquinoline are converted into 95 mg of product.

¹H-NMR (300 MHz, CDCl₃): δ=1.35 (s, 3H), 1.60 (s, 3H), 2.45 (d, 1H),2.80 (d, 1H), 5.00 (s, 1H), 6.20 (d, 1H), 6.95-7.1 (m, 3H), 7.30 (m,2H), 7.50 (m, 2H), 8.00 (d, 1H), 8.45 (d, 1H), 8.95 (m, 1H).

1-[(Quinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

Analogously to Example 13, 95 mg of1,1,1-trifluoro-4-phenyl-2-[(quinolin-5-yl)iminomethyl]-4-methylpentan-2-olis converted into 90 mg of product.

¹H-NMR (300 MHz, CDCl₃): δ=1.45 (s, 3H), 1.60 (s, 3H), 2.15 (d, 1H),2.20 (d, 1H), 3.25 (br., 1H), 4.95 (br. d, 1H), 5.20 (d, 1H), 6.90 (dd,1H), 7.10 (t, 1H), 7.25-7.35 (m, 4H), 7.40 (d, 1H), 7.60 (m, 2H), 8.15(d, 1H), 8.90 (m, 1H).

Example 155-{[2-Hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino1-quinolin-2(1H)-one5-{[2-Hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentylidene]amino}quinolin-2(1H)-one

Analogously to Example 13, 600 mg of2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 337 mg of5-aminoquinolin-2(1H)-one (52313) are converted into 570 mg of product.

¹H-NMR (300 MHz, CDCl₃): δ=1.35 (s, 3H), 1.55 (s, 3H), 2.40 (d, 1H),2.80 (d, 1H), 4.70 (br. s, 1H), 5.80 (d, 1H), 6.75 (d, 1H), 7.05 (t,1H), 7.15 (t, 2H), 7.30 (m, 4H), 8.00 (d, 1H), 9.05 (br. s, 1H).

5-{[2-Hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

Analogously to Example 13, 23 mg of5-{[2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentylidene]amino}quinolin-2(1H)-oneis converted into 11 mg of product.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.35 (s, 3H), 1.50 (s, 3H), 2.00 (d, 1H),2.10 (d, 1H), 5.35 (d, 1H), 6.05 (s, 1H), 6.20 (d, 1H), 6.40 (d, 1H),6.55 (t, 1H), 7.25 (m, 2H), 7.45 (d, 1H), 8.20 (d, 1H), 11.60 (br.s,1H).

Example 161-[(2-Methoxyquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol1,1,1-Trifluoro-4-phenyl-2-[(2-methoxyquinolin-5-yl)iminomethyl]-4-methylpentan-2-ol

Analogously to Example 13, 200 mg of2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 122 mg of5-amino-2-methoxyquinoline are converted into 190 mg of product.

¹H-NMR (300 MHz, CDCl₃): δ=1.35 (s, 3H), 1.55 (s, 3H), 2.45 (d, 1H),2.80 (d, 1H), 4.10 (s, 3H), 5.00 (s, 1H), 6.10 (d, 1H), 6.90 (d, 1H),6.95 (t, 1H), 7.05 (t, 2H), 7.30 (d, 2H), 7.35 (t, 1H), 7.70 (d, 1H),8.30 (d, 1H).

1-[(2-Methoxyquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

Analogously to Example 13, 185 mg of1,1,1-trifluoro-4-phenyl-2-[(2-methoxyquinolin-5-yl)iminomethyl]-4-methylpentan-2-olis converted into 127 mg of product.

¹H-NMR (300 MHz, CDCl₃): δ=1.45 (s, 3H), 1.60 (s, 3H), 2.15 (d, 1H),2.20 (d, 1H), 3.10 (s, 1H), 4.10 (s, 3H), 4.75 (br. d, 1H), 5.20 (d,1H), 6.75 (d, 1H), 6.85 (d, 1H), 7.1 (t, 1H), 7.25-7.45 (m, 4H), 7.50(t, 1H), 8.00 (d, 1H).

Example 171-[(Phenylamino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol1,1,1-Trifluoro-4-phenyl-2-[(phenyl)iminomethyl]-4-methylpentan-2-ol

Analogously to Example 1, 200 mg of2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 64 μl ofaniline are converted into 180 mg of product.

¹H-NMR (300 MHz, CDCl₃): δ=1.35 (s, 3H), 1.50 (s, 3H), 2.35 (d, 1H),2.70 (d, 1H), 5.05 (s, 1H), 6.65 (d, 2H), 7.05 (t, 1H), 7.15-7.30 (m,7H).

1-[(Phenylamino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

9.6 ml of a 1 M titanium tetrachloride-CH₂Cl₂ solution is added in dropsto a solution of 175 mg of1,1,1-trifluoro-4-phenyl-2-[(phenyl)iminomethyl]-4-methylpentan-2-ol in160 ml of CH₂Cl₂ at −78° C. First, it is stirred for 1 hour at −78° C.,and after another 10 ml of titanium tetrachloride-CH₂Cl₂ solution isadded, it is stirred for 60 hours at room temperature.

The batch is mixed with saturated NaHCO₃, the phases are separated, theaqueous phase is extracted with CH₂Cl₂, the combined organic phases aredried (Na₂SO₄) and concentrated by evaporation in a vacuum. Columnchromatography on silica gel with cyclohexane-ethyl acetate yields 45 mgof product.

¹H-NMR (CDCl₃): δ=1.40 (s, 3H), 1.50 (s, 3H), 2.00 (d, 1H), 2.20 (d,1H), 3.40 (s, 1H), 3.80 (d, 1H), 4.95 (d, 1H), 6.80 (d, 2H), 6.85 (t,1H), 7.15 (m, 1H), 7.20-7.30 (m, 4H), 7.40 (d, 1H).

Example 184-{[2-Hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-(trifluoromethyl)benzonitrile1,1,1-Trifluoro-4-phenyl-2-[(4-cyano-3-(trifluoromethyl)phenyl)iminomethyl]-4-methylpentan-2-ol

Analogously to Example 13, 120 mg of2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 78 mg of4-cyano-3-(trifluoromethyl)aniline are converted into 71 mg of product.

¹H-NMR (300 MHz, CDCl₃): δ=1.35 (s, 3H), 1.55 (s, 3H), 2.40 (d, 1H),2.75 (d, 1H), 4.55 (s, 1H), 6.75 (dd, 1H), 6.95 (d, 1H), 7.10 (t, 1H),7.20 (m, 3H), 7.30 (m, 2H), 7.70 (d, 1H).

4-{[2-Hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-(trifluoromethyl)benzonitrile

Analogously to Example 13, 71 mg of1,1,1-trifluoro-4-phenyl-2-[(4-cyano-3-(trifluoromethyl)phenyl)iminomethyl]-4-methylpentan-2-olis converted into 58 mg of product.

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (s, 3H), 1.50 (s, 3H), 2.15 (s, 2H),2.60 (s, 1H), 5.05 (d, 1H), 5.10 (d, 1H), 6.85 (dd, 1H), 7.00 (d, 1H),7.20 (s, 2H), 7.35 (m, 1H), 7.40 (d, 1H), 7.60 (d, 1H).

Example 195-{[5-Bromo-2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one(2-Bromophenyl)-acetonitrile

25 g (100 mmol) of 2-bromobenzyl bromide is mixed in 100 ml ofN,N-dimethylformamide and 64 ml of water with 9.75 g (150 mmol) ofpotassium cyanide and stirred overnight at room temperature. Thereaction mixture is poured into ice water. After 3× extraction withmethyl-tert butyl ether, the combined organic extracts are washed withbrine, dried, and the solvent is spun off. The residue ischromatographed on silica gel (mobile solvent ethyl acetate/hexane).18.9 g (96.4%) of the desired compound is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=3.85 (2H), 7.23 (1H), 7.48 (1H), 7.55 (1H),7.62 (1H).

2-(2-Bromophenyl)-2-methyl-propionitrile

18.9 g (96.41 mmol) of (2-bromophenyl)-acetonitrile and 31.41 g (221.74mmol) of methyl iodide are dissolved in 150 ml of N,N-dimethylformamide.At 0° C., 8.87 g (221.74 mmol) of sodium hydride (as 60% suspension inoil) is added in portions, and the batch is stirred overnight at roomtemperature. The reaction mixture is poured into ice water and worked upas usual. Since the compound that is isolated after chromatography (20.9g) still contains 2-(2-bromophenyl)-propionitrile in addition to thedesired product, the entire amount is reacted another time with the sameamounts of reagent. This reaction also yields only material that stillcontains mono-methyl compound. After another alkylation with 15 g ofmethyl iodide and 4.45 g of sodium hydride in 150 ml ofN,N-dimethylformamide, 18.57 g of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.91 (6H), 7.20 (1H), 7.35 (1H), 7.49 (1H),7.68 (1H).

2-(2-Bromophenyl)-2-methyl-propanal

18.57 g (82.21 mmol) of 2-(2-bromophenyl)-2-methyl-propionitrile isreduced in 325 ml of toluene with 102.72 ml of a 1.2 M DIBAH solution intoluene, specifically as described in Example 3. After working-up, 18.17g (97.34%) of the desired aldehyde is isolated, which is incorporated incrude form into the next stage.

¹H-NMR (300 MHz, CDCl₃): δ=1.51 (6H), 7.20 (1H), 7.33-7.45 (2H), 7.61(1H), 9.8 (1H).

(E/Z)-4-(2-Bromophenyl)-4-methylpent-2-enoic acid ethyl ester

18.17 g (80.02 mmol) of 2-(2-bromophenyl)-2-methyl-propanal is subjectedanalogously to the Horner-Wittig reaction that is described in Example3. After the working-up and subsequent chromatography on silica gel(mobile solvent ethyl acetate/hexane) described there, 22.3 g (81.67%)of the desired product is isolated.

(E/Z)-4-(2-Bromophenyl)-4-methylpent-2-enoic acid

22.3 g (65.349 mmol) of (E/Z)-4-(2-bromophenyl)-4-methylpent-2-enoicacid ethyl ester is saponified with 650 ml of sodium hydroxide solution(1N in ethanol/water 2:1) as described in Example 3. After theworking-up, 14.32 g (69.9%) of the desired acid is isolated.

4-(2-Bromophenyl)-4-methyl-2-oxo-pentanoic acid

14.32 g (45.72 mmol) of (E/Z)-4-(2-bromophenyl)-4-methylpent-2-enoicacid is reacted with the aid of sulfuric acid in glacial acetic acid, asdescribed in Example 3, to form the desired ketocarboxylic acid. 13 g(99.6%) is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.60 (6H), 3.91 (2H), 7.09 (1H), 7.30 (1H),7.49 (1H), 7.57 (1H).

4-(2-Bromophenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester

13 g (45.59 mmol) of 4-(2-bromophenyl)-4-methyl-2-oxo-pentanoic acid isreacted with ethanol and concentrated sulfuric acid to form ester. Afterimplementation and working-up (see Example 3), 13.01 g (91.1%) of thedesired compound is obtained after chromatography on silica gel.

¹H-NMR (300 MHz, CDCl₃): δ=1.30 (3H), 1.60 (6H), 3.72 (2H), 4.17 (2H),7.05 (1H), 7.27 (1H), 7.47 (1H), 7.57 (1H).

4-(2-Bromophenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol

13 g (41.5 mmol) of 4-(2-bromophenyl)-4-methyl-2-oxo-pentanoic acidethyl ester is reacted with Rupperts reagent, as described in Example 3.After working-up and chromatography on silica gel (mobile solvent ethylacetate/hexane), 16.15 g (85.6%) of the desired compound is isolated.

73.6 ml (88.39 mmol) of a DIBAH solution (1.2 M in toluene) is added indrops (35 minutes) to a solution of 6.1 g (35.45 mmol) of theabove-described trifluoromethyl alcohol in 148 ml of toluene at −10° C.After 30 minutes of stirring at a temperature of between −10° C. and −5°C., 24.2 ml of isopropanol and then water are carefully added in dropsat −10° C. After two hours of vigorous stirring at room temperature, theprecipitate that is produced is suctioned off on a G4 frit, washed withethyl acetate, and the filtrate is spun in until a dry state is reached.The residue (regioisomeric mixture of the two silyl ethers; 14.5g=95.4%=35.08 mmol) is reacted with tetrabutylammoniumfluoride-trihydrate in tetrahydrofuran at room temperature as describedin Example 3. After the conventional working-up and chromatography, 5.26g of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.62 (3H), 1.70 (3H), 2.19 (1H), 2.90-3.01(2H), 3.27-3.89 (1H), 3.59 (1H), 7.09 (1H), 7.30 (1H), 7.53 (1H), 7.60(1H).

4-(2-Bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal

2 g (5.86 mmol) of4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentan-1-ol isoxidized with SO₃-pyridine complex, as described in Example 1. 1.72 g(86.8 mmol) of the desired aldehyde is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.60 (6H), 2.29 (1H), 3.65 (1H), 3.78 (1H),7.09 (1H), 7.25 (1H), 7.34 (1H), 7.58 (1H), 9.20 (1H).

4-{[4-(2-Bromophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]-amino}}isoquinolin-1(2H)-one

200 mg (0.589 mmol) of4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal isstirred for five days at room temperature with 94.3 mg (0.589 mmol) of5-aminoisoquinolin-1(2H)-one (Example 2) in 0.86 ml of glacial aceticacid. After the conventional working-up and chromatography on silica gel(mobile solvent ethyl acetate/hexane), 170.8 mg (60.2%) of the desiredcompound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.59 (3H), 1.70 (3H), 2.29 (1H), 3.86 (1H),4.89 (1H), 6.58 (1H), 6.70-6.90 (3H), 7.15-7.37 (3H), 7.48 (1H), 7.59(1H), 8.30 (1H), 11.00 (1H).

5-{[5-Bromo-2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one

50 mg (0.104 mmol) of4-{[4-(2-bromophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}}isoquinolin-1(2H)-oneis mixed with one milliliter of a 1 M solution of BBr₃ indichloromethane and stirred for one and three quarters hours at roomtemperature. After the conventional working-up (see Example 2) and afterchromatography on silica gel (mobile solvent methanol/dichloromethane),49.2 mg (98.4%) of the desired compound is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.67 (3H), 1.79 (3H), 2.09 (1H), 2.21 (1H),5.48 (1H), 6.02 (1H), 6.26 (1H), 6.81 (1H), 7.00-7.30 (5H), 7.49-7.62(2H), 11.25 (1H).

With use of the corresponding starting aldehydes and amines that aredescribed in the examples above, the following cyclic compounds areproduced via the imines.

Example 205-Bromo-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The product is obtained after cyclization, as described in Example 19.

¹H-NMR (300 MHz, CD₃OD): δ=1.73 (3H), 1.88 (3H), 2.10-2.30 (2H), 5.30(1H), 6.39 (1H), 6.85 (1H), 7.01 (1H), 7.24 (1H), 7.48 (1H), 7.58 (1H),8.13 (1H).

Example 215-Bromo-4,4-dimethyl-1-propylamino-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The product is obtained after cyclization, as described in Example 19.

¹H-NMR (300 MHz, CD₃OD): δ=0.90-1.02 (3H), 1.48-1.60 (2H), 1.63 (3H),1.70 (3H), 1.91 (1H), 2.15 (1H), 2.65-2.78 (1H), 2.91-3.05 (1H), 7.12(1H), 7.45 (1H), 7.56 (1H).

Example 225-Bromo-1-[(3-hydroxypropyl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The product is obtained after cyclization, as described in Example 19.

¹H-NMR (300 MHz, CD₃OD): δ=1.63 (3H), 1.71 (3H), 1.94 (1H), 1.99-2.11(2H), 2.17 (1H), 2.84-2.98 (1H), 3.09-3.20 (1H), 3.55 (2H), 7.13 (1H),7.49 (1H), 7.59 (1H).

Example 235-{[8-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one

The product is obtained after cyclization, as described in Example 19.

MS (ES+, ACN/H₂O+0.01% TFA): 437 (100%)

Example 244-{[7-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-fluoro-2,3-dihydroisoindol-1-one

The product is obtained after cyclization, as described in Example 19.

¹H-NMR (300 MHz, CD₃OD): δ=1.58 (3H), 1.65 (3H), 2.01-2.10 (2H),4.20-4.45 (2H), 5.10 (1H), 6.70-6.89 (4H).

Example 255-{[6-Fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one

The product is obtained after cyclization, as described in Example 3.

¹H-NMR (300 MHz, CD₃OD): δ=1.53 (3H), 1.58 (3H), 2.14 (2H), 3.99 (3H),5.15 (1H), 6.84 (1H), 6.95 (1H), 7.00-7.10 (2H), 7.18 (1H), 7.39 (1H),7.69 (1H).

The product that is obtained is separated into its enantiomers(Chiralpak AD 20μ; mobile solvent hexane/ethanol/DEA), and the latter isthen used in the ether cleavage (analogously to Example 3):

5-{[6-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one(CIs, Enantiomer A)

¹H-NMR (300 MHz, CD₃OD): δ=1.62 (3H), 1.72 (3H), 2.04-2.21 (2H), 5.13(1H), 6.75-6.92 (3H), 7.05 (1H), 7.18 (1H), 7.39 (1H), 7.69 (1H).

5-{[6-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino1-isoquinolin-1(2H)-one (CIs, Enantiomer B)

¹H-NMR (300 MHz, CD₃OD): δ=1.62 (3H), 1.72 (3H), 2.04-2.21 (2H), 5.13(1H), 6.75-6.92 (3H), 7.05 (1H), 7.18 (1H), 7.39 (1H), 7.69 (1H).

Example 264-{[6-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one

The product is obtained after cyclization and ether cleavage, asdescribed in Example 3.

¹H-NMR (300 MHz, CD₃OD): δ=1.60 (3H), 1.69 (3H), 1.99-2.20 (2H),4.23-4.45 (2H), 5.13 (1H), 6.80-7.03 (3H), 7.18 (1H), 7.39 (1H).

Example 276-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol3-Chloro-2-methoxybenzylcyanide

39.4 g (221.3 mmol) of NBS and 100 mg of benzoyl peroxide are added to31.6 g (201.7 mmol) of 3-chloro-2-methoxytoluene in 500 ml of CCl₄. Itis refluxed over 16 hours, allowed to cool and filtered. Solvent isremoved from the filtrate, and the filtrate is dissolved in 214 ml ofN,N-dimethylformamide and 142 ml of water. 20.9 g (322.1 mmol) ofpotassium cyanide is added at 0° C. and stirred over 16 hours. Thereaction mixture is diluted with water and extracted several times withtert-butyl-methyl ether. The organic phase is washed several times withsaturated sodium chloride solution and dried on sodium sulfate. Thesolvent is removed in a vacuum and after chromatographic purification onsilica gel (hexane/ethyl acetate 20%), 29.7 g of product is obtained.

¹H-NMR (CDCl₃): δ=3.76 (s, 2H), 3.95 (s, 3H), 7.08 (t, 1H), 7.31 (d,1H), 7.37 (d, 1H).

4-(3-Chloro-2-methoxy-phenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol

29.7 g (163.7 mmol) of 4-chloro-2-methoxybenzylcyanide and 46.5 g (327.4mmol) of methyl iodide in 260 ml DMF are mixed at 0° C. in portions with13.2 g (327.4 mmol) of sodium hydride (60% in oil). It is stirredovernight and then mixed with water and ethyl acetate. The phases areseparated, and the aqueous phase is extracted several times with ethylacetate. It is washed with water and saturated sodium chloride solution,dried with sodium sulfate, and concentrated by evaporation in a vacuum.After chromatography on silica gel (hexane/ethyl acetate 95:5), 32.4 gof 2-(4-chloro-2-methoxy-phenyl)-2-methylpropionitrile is obtained as acolorless oil. 7 g (33.4 mmol) of the nitrile is slowly mixed in tolueneat −78° C. with 41.6 ml (50.1 mmol) of diisobutylaluminum hydridesolution (20% in toluene), and after 3 hours at −78° C., 5.55 ml ofisopropanol is added in drops. It is allowed to heat to −5° C., and 380ml of a 10% aqueous tartaric acid solution is added. After dilution withether, it is stirred vigorously, the organic phase is separated, and theaqueous phase is extracted several times with ether. It is washed withbrine, dried with sodium sulfate and concentrated by evaporation in avacuum. After chromatography on silica gel (hexane/ethyl acetate 95:5),7.1 g of 2-(4-chloro-methoxy-phenyl)-2-methylpropanal is obtained as acolorless oil. A solution of 8.95 g (33.4 mmol) of2-diethylphosphono-2-ethoxyacetic acid-ethyl ester in 30 ml oftetrahydrofuran is mixed while being cooled with ice within 20 minuteswith 19 ml (38 mmol) of a 2 M solution of lithium diisopropylamide intetrahydrofuran-heptane-toluene, and it is stirred for 15 minutes at 0°C. Within 30 minutes, a solution of 7.1 g (33.4 mmol) of2-(3-chloro-2-methoxyphenyl)-2-methylpropanal in 27 ml oftetrahydrofuran is added in drops at 0° C. After 20 hours at roomtemperature, water is added, and it is extracted several times withether and ethyl acetate. It is washed with saturated ammonium chloridesolution, dried (Na₂SO₄) and concentrated by evaporation. The crudeproduct is purified by column chromatography on silica gel (hexane/ethylacetate 10%), and 8.5 g of4-(3-chloro-2-methoxy-phenyl)-4-methyl-3-ethoxy-2-ene-valeric acid ethylester is obtained. The intermediate product is saponified with 80 ml of3 M sodium hydroxide solution/160 ml of ethanol. 5.3 g of acid, which isstirred with 80 ml of 2N sulfuric acid at 90° C. over 16 hours, isobtained. After cooling, it is made basic with potassium carbonate,washed with ether, and acidified with hydrochloric acid. Afterextraction with ethyl acetate, washing with saturated sodium chloridesolution and removal of the solvent, 4.0 g of4-(3-chloro-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid is obtained.6.6 g (24.3 mmol) of4-(3-chloro-2-methoxy-phenyl)-4-methyl-2-oxo-valeric acid and 2.74 ml(51.4 mmol) of sulfuric acid (96%) are refluxed in 150 ml of ethanol for5 hours. The batch is concentrated by evaporation in a vacuum, and theresidue is taken up in saturated sodium bicarbonate solution. It isextracted several times with ethyl acetate, washed with saturated sodiumbicarbonate solution, dried (sodium sulfate) and concentrated byevaporation in a vacuum. After chromatographic purification on silicagel (hexane/ethyl acetate 10%), 5.9 g of4-(3-chloro-2-methoxy-phenyl)-4-methyl-2-oxo-valeric acid-ethyl ester isobtained. This ester and 3.4 g (23.8 mmol) of(trifluoromethyl)-trimethylsilane in 34 ml of THF are mixed with 49 mgof tetrabutylammonium fluoride at 0° C. It is stirred for 16 hours atroom temperature, and then the reaction mixture is added to water. It isextracted several times with ethyl acetate, washed with saturated sodiumchloride solution, dried with sodium sulfate, and concentrated byevaporation in a vacuum. 2.96 g of4-(3-chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valericacid-ethyl ester is obtained as a yellow oil. This oil is mixed in 24 mlof diethyl ether at 0° C. with 510 mg of lithium aluminum hydride andstirred for 4 more hours at room temperature. 20 ml of saturated sodiumbicarbonate solution is carefully added to the batch at 0° C., and it isvigorously stirred for 1 more hour. It is extracted several times withmethyl tert-butyl ether, washed with water and saturated sodium chloridesolution, dried with sodium sulfate and concentrated by evaporation in avacuum. The crude product is mixed in 33 ml of THF with 1.83 (5.79 mmol)of tetrabutylammonium fluoride trihydrate, and it is stirred for 16hours. It is poured into ice water, extracted several times with methyltert-butyl ether, washed with saturated sodium chloride solution, driedwith sodium sulfate and concentrated by evaporation in a vacuum. Afterchromatographic purification on silica gel (hexane/ethyl acetate 25%),1.81 g of4-(3-chloro-2-methoxy-phenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diolis obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.47 (s, 3H), 1.56 (s, 3H), 2.21 (d, 1H),2.54 (d, 1H), 2.91 (s, 1H), 3.31 (dd, 1H), 3.42 (d, 1H), 4.01 (s, 3H),7.00 (t, 1H), 7.20-7.35 (m, 2H)

4-(3-Chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal

1.87 g (18.5 mmol) of triethylamine and, in portions over 10 minutes,1.17 g (7.4 mmol) of pyridine SO₃ complex are added to 1.2 g (3.7 mmol)of diol in 24 ml of dichloromethane and 6.4 ml of DMSO. It is stirredover 5 hours, and 30 ml of saturated ammonium chloride solution isadded. The mixture is stirred for another 15 minutes, the phases areseparated, and it is extracted with methyl tert-butyl ether. It iswashed with water and dried on sodium sulfate. The solvent is removed ina vacuum, and after chromatographic purification on silica gel(hexane/ethyl acetate, 0-50%), 0.98 g of product is obtained.

¹H-NMR (CDCl₃): δ=1.44 (s, 3H), 1.50 (s, 3H), 2.29 (d, 2H), 3.28 (d,1H), 3.55 (s, 1H), 4.01 (s, 3H), 6.95 (t, 1H), 7.07 (dd, 1H), 7.30 (dd,1H), 8.90 (s, 1H).

1,1,1-Trifluoro-4-(3-chloro-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol

125 mg (0.385 mmol) of4-(3-chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanalis mixed in 0.7 ml of glacial acetic acid with 51.3 mg (0.385 mmol) of4-aminoindazole, and it is stirred overnight at room temperature. Afterconcentration by evaporation until a dry state is reached, it ischromatographed on a Flashmaster. 11.9 mg (74.1%) of the desiredcompound is isolated.

6-Chloro-1-[(1H-indazol-4-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

116.9 mg (0.285 mmol) of imine is dissolved in 2.6 ml of dichloromethaneand mixed at −25° C. with 1.13 ml of a 1 M solution of titaniumtetrachloride in dichloromethane. After six more hours of stirringbetween −20° C. and +10° C., it is mixed with saturated sodiumbicarbonate solution and extracted with ethyl acetate. After drying withsodium sulfate, the organic phases are spun in until a dry state isreached. Chromatography of the residue on the Flashmaster yields 91.9 mg(78.6%) of the desired cyclic compound (together with the Deschlorocompound).

6-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

69.9 mg (0.159 mmol) of6-chloro-1-[(1H-indazol-4-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-olis mixed with 1.45 ml of a one-molar solution of BBr₃ indichloromethane, and it is stirred for five hours at room temperature.After the conventional working-up, the residue is chromatographed on aFlashmaster. 28.1 mg (41.5%) of the desired compound is isolated.

Melting point: 112-120° C.

Example 28cis-7-Chloro-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol4-(4-Chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal2-(4-Chlorophenyl)-2-methylpropanal

10 g of 4-chlorobenzyl cyanide and 14.3 ml of methyl iodide in 140 ml ofDMF are mixed at 0° C. in portions with sodium hydride (60% in oil). Itis stirred overnight and then mixed with water and ethyl acetate. Thephases are separated, and the aqueous phase is extracted with ethylacetate.

It is thoroughly extracted with water, washed with brine, dried withsodium sulfate and concentrated by evaporation in a vacuum. Afterchromatography on silica gel (hexane/ethyl acetate 95:5), 11.73 g of2-(4-chlorophenyl)-2-methylpropionitrile is obtained as a colorless oil.The latter is slowly mixed in toluene at −78° C. with 55.4 ml ofdiisobutylaluminum hydride solution (20% in toluene), and after 4 hoursat −78° C., 50 ml of ethyl acetate was added in drops. It is stirredovernight while being heated to room temperature, and water is added.After filtration through diatomaceous earth, the phases are separated,and the aqueous phase is extracted with ethyl acetate. It is washed withwater and brine, dried with sodium sulfate, and concentrated byevaporation in a vacuum. After chromatography on silica gel(hexane/ethyl acetate 95:5), 10.2 g of2-(4-chlorophenyl)-2-methylpropanal is obtained as a colorless oil.

¹H-NMR (300 MHz, CDCl₃), δ=1.46 (s, 6H), 7.20 (d, 1H), 7.29-7.43 (m,3H), 9.48 (s, 1H)

4-(4-Chlorophenyl)-4-methyl-2-oxo-valeric acid

A solution of 15.04 g of 2-diethylphosphono-2-ethoxyacetic acid-ethylester in 50 ml of tetrahydrofuran is mixed with 30 ml of a 2 M solutionof lithium diisopropylamide in tetrahydrofuran-heptane-toluene whilebeing cooled with ice within 20 minutes, and it is stirred for 15minutes at 0° C. Within 30 minutes, a solution of 10.2 g of2-(4-chlorophenyl)-2-methylpropanal in 50 ml of tetrahydrofuran is addedthereto at 0° C. After 20 hours at room temperature, 2N sulfuric acid isadded, it is extracted with ethyl acetate, dried (Na₂SO₄) andconcentrated by evaporation. The crude product is saponified with 200 mlof 2 M sodium hydroxide solution/400 ml of ethanol. 13.8 g of acid,which is refluxed for 3 hours with 300 ml of 2N sulfuric acid and 100 mlof glacial acetic acid while being stirred vigorously, is obtained.After extraction with ethyl acetate and washing with water, 10.9 g of4-(4-chlorophenyl)-4-methyl-2-oxo-valeric acid is obtained as a red oil.

¹H-NMR (300 MHz, CDCl₃), δ=1.47 (s, 6H), 3.28 (s, 2H), 7.28 (m, 4H),7.73 (bs, 1H)

4-(4-Chlorophenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol

Analogously to the synthesis of4-(3-chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal(Example 27), 4.22 g of4-(4-chlorophenyl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol isobtained as a colorless oil by esterification of 10.9 g of4-(4-chlorophenyl)-4-methyl-2-oxo-valeric acid in ethanol/sulfuric acid,reaction of the product with (trifluoromethyl)trimethylsilane andtetrabutylammonium fluoride and reduction of the formed hydroxy esterwith lithium aluminum hydride.

¹H-NMR (CDCl₃), 6 (Ppm)=1.39 (s, 3H), 1.49 (s, 3H), 2.07 (d, 1H), 2.19(d, 1H), 2.83 (bs, 1H), 3.27 (d, 1H), 3.41 (d, 1H), 7.26-7.38 (m, 4H).

4-(4-Chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal

6.8 ml (33.3 mmol) of triethylamine and, in portions over 20 minutes,1.5 g of pyridine SO₃ complex are added to 2 g (6.7 mmol) of diol in 50ml of dichloromethane and 22 ml of DMSO. It is stirred over 5 hours, and40 ml of saturated ammonium chloride solution is added. The mixture isstirred for another 15 minutes, the phases are separated, and it isextracted with dichloromethane. It is washed with water and dried onsodium sulfate. The solvent is removed in a vacuum, and afterchromatography on silica gel (hexane/ethyl acetate 0-30%), 1.27 g ofproduct is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.34 (s, 3H), 1.44 (s, 3H), 2.34 (d, 2H),2.66 (d, 1H), 3.64 (s, 1H), 7.23-7.31 (m, 4H), 8.90 (s, 1H).

7-Chloro-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

Starting from the above-described aldehyde, the desired compound issynthesized via the imine as described in Example 83.

¹H-NMR (300 MHz, CDCl₃): δ=1.45 (s, 3H), 1.63 (s, 3H), 2.19 (d, 1H),2.31 (d, 1H), 2.87 (s, 3H), 5.05 (d, 1H), 5.98 (d, 1H), 6.78 (d, 1H),7.28-7.37 (m, 4H), 7.76 (t, 1H), 9.36 (s, 1H).

Example 295,8-Difluoro-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol4-(2,5-Difluorophenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol

5.4 g (15.5 mmol) of4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acidethyl ester (WO 02/10143) is dissolved at 0° C. in diethyl ether andmixed within 20 minutes with 1.76 g (46.5 mmol) of lithium aluminumhydride. It is allowed to stir at room temperature for 4 hours, and thenenough saturated NaHCO₃ solution is carefully added until no more gasgeneration can be observed. The mixture is diluted with ethyl acetate,stirred for 15 more minutes, and then the formed precipitate is filteredoff. It is concentrated by evaporation and chromatographed on silica gelwith hexane/ethyl acetate (50%). 2.45 g of2,5-difluorophenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol isobtained as a weakly yellowish crystallizing oil.

4-(2,5-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal

800 mg (2.8 mmol) of4-(2,5-difluorophenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol isintroduced into 20 ml of dichloromethane, and at 0° C., 9.5 ml of DMSOand 1.95 ml of triethylamine are added. The solution is slowly mixedwith 1.34 g (8.4 mmol) of SO₃-pyridine complex, and it is stirred for 2hours at 0° C. The mixture is dispersed between saturated ammoniumchloride solution and MTBE, the phases are separated, and the aqueousphase is extracted with MTBE. The combined organic phases are washedwith water and saturated NaCl solution and dried with NaSO₄. It isconcentrated by evaporation and chromatographed on silica gel withhexane/ethyl acetate (30%). 710 mg of the desired product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.41 (s, 3H), 1.48 (s, 3H), 2.39 (d, 2H),3.02 (d, 1H), 3.61 (s, 1H), 6.84-7.18 (m, 3H), 9.23 (s, 1H).

5,8-Difluoro-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The desired compound is synthesized via the imine (diastereomer A).

¹H-NMR (300 MHz, CDCl₃): δ=1.51 (s, 3H), 1.68 (s, 3H), 2.11 (d, J=15 Hz,1H), 2.23 (d, J=15 Hz, 1H), 2.84 (s, 3H), 4.23 (s, br, 1H), 4.84 (d, J=8Hz, 1H), 5.32 (d, J=8 Hz, 1H), 6.80-6.90 (m, 1H), 6.95-7.02 (m, 1H),7.05 (d, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.77 (dd, J=8 Hz/8 Hz, 1H),9.19 (s, 1H).

Example 305-{[4,4-Dimethyl-6-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one5-Aminoquinolin-2(1H)-one

4.5 g of 5-nitroquinolin-2(1H)-one (Chem. Pharm. Bull. (1981), 29, pp.651-56) is hydrogenated in 200 ml of ethyl acetate and 500 ml ofmethanol in the presence of 450 mg of palladium on activated carbon as acatalyst under normal pressure with hydrogen until the reaction iscompleted. The catalyst is removed by filtration through diatomaceousearth, and the reaction solution is concentrated by evaporation in avacuum. 3.8 g of the title compound is obtained as a yellow solid.

¹H-NMR (DMSO): δ=5.85 (bs, 2H), 6.27 (d, 1H), 6.33 (d, 1H), 6.43 (d,1H), 7.10 (t, 1H), 8.07 (d, 1H), 11.39 (bs, 1H)

5-{[4,4-Dimethyl-6-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

Analogously to Example 3, the corresponding imine is produced startingfrom 500 mg of4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanaland 260 mg of 5-aminoquinolin-2(1H)-one. By reaction of 80 mg of theimine with 0.5 ml of titanium tetrachloride (1 M in dichloromethane), 20mg of the title compound is obtained.

Examples 31 and 325-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one,Diastereomer B5-{[2,5-Dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one,Diastereomer A4-(2-Methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal

19.3 g of 4-(2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester(WO 00/32584) in 630 ml of diethyl ether is mixed in portions at 0° C.with 3.3 g of lithium aluminum hydride. After stirring for 10 hours, itis added to saturated bicarbonate solution and filtered throughdiatomaceous earth. The phases are separated, and the aqueous phase isextracted with ethyl acetate. The organic phase is washed with water andbrine, dried (Na₂SO₄) and concentrated by evaporation. Afterchromatography on silica gel (hexane/ethyl acetate 0->10%), 16.3 g ofdiol is obtained as a yellow oil.

2.0 g of diol, 5.2 ml of triethylamine and 5.12 g of sulfurtrioxide-pyridine complex in 24 ml of DMSO are stirred at roomtemperature for 48 hours. It is added to 0.5N hydrochloric acid andextracted with ethyl acetate. The organic phase is washed with water andbrine, dried (Na₂SO₄) and concentrated by evaporation in a vacuum. Afterchromatography on silica gel (hexane/ethyl acetate 0->3%), 1.44 g of4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal isobtained as a yellow oil.

¹H-NMR (300 MHz, CDCl₃), δ=1.40 (s, 3H), 1.47 (s, 3H), 2.2 (d, 1H), 3.46(d, 1H), 3.60 (s, 1H), 3.88 (s, 3H), 6.83-6.94 (m, 2H), 7.13 (dd, 1H),7.24 (dt, 1H), 8.94 (s, 1H)

5-}[4,4-Dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one,Diastereomer B and5-{[2,5-Dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one,Diastereomer A: Analogously to Example 2, the corresponding imine isproduced starting from 1.0 g of4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and553 mg of 5-aminoquinolin-2(1H)-one. 21 mg of5-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-oneas fraction 1 and 5 mg of5-{[2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-oneas fraction 2 are obtained by reaction of 50 mg of the imine with 0.22ml of BBr₃ (1N in dichloromethane).

Fraction 1: ¹H-NMR (300 MHz, CD₃OD): δ=1.50 (s, 3H), 1.63 (s, 3H), 2.04(d, 1H), 2.12 (d, 1H), 3.83 (s, 3H), 5.17 (s, 1H), 6.48 (d, 1H), 6.60(d, 1H), 6.67 (d, 1H), 6.90 (d, 1H), 6.92 (d, 1H), 7.10 (t, 1H), 7.35(t, 1H), 8.20 (d, 1H)

Flash point=269-270° C.

Fraction 2: ¹H-NMR (300 MHz, CD₃OD): δ=1.39 (s, 3H), 1.52 (s, 3H), 2.05(d, 1H), 2.23 (d, 1H), 5.28 (s, 1H), 6.38 (d, 1H), 6.58 (d, 1H), 6.68(d, 1H), 6.92 (d, 1H), 7.00 (d, 1H), 7.11 (t, 1H), 7.38 (t, 1H), 8.14(d, 1H)

Examples 33 and 34(−)-5-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one(+)-5-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

Separation of(+/−)-5-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one:

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10,vvv). The (−)-enantiomer: MS (ESI): M⁺+1=433, [α]_(D)−70.1° °(c=1.0,CHCl₃) and the (+)-enantiomer: MS (ESI): M⁺+1=433, [α]_(D)+78.5°°(c=1.0, CHCl₃) are thus obtained.

Example 35(+)-5-{[2,5-Dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one,Diastereomer B

Analogously to Example 3, 5 mg of the title compound is obtained byreaction of 50 mg of(+)-5-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-oneand 0.22 ml of BBr₃ (1 M in dichloromethane).

¹H-NMR (300 MHz, CD₃OD): δ=1.56 (s, 3H), 1.68 (s, 3H), 2.06 (d, 1H),2.15 (d, 1H), 5.15 (s, 1H), 6.51 (d, 1H), 6.62 (d, 1H), 6.68 (d, 1H),6.70 (d, 1H), 6.81 (d, 1H), 6.95 (t, 1H), 7.37 (t, 1H), 8.23 (d, 1H)

Example 36(−)-5-{[2,5-Dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino1-quinolin-2(1H)-one, Diastereomer B

Analogously to Example 3, 32 mg of the title compound is obtained byreaction of 70 mg of(−)-5-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-oneand 0.32 ml of BBr₃ (1 M in dichloromethane).

¹H-NMR (300 MHz, CD₃OD): δ=1.57 (s, 3H), 1.68 (s, 3H), 2.05 (d, 1H),2.14 (d, 1H), 5.15 (s, 1H), 6.51 (d, 1H), 6.62 (d, 1H), 6.67 (d, 1H),6.68 (d, 1H), 6.81 (d, 1H), 6.95 (t, 1H), 7.37 (t, 1H), 8.22 (d, 1H)

Example 375-{[7-Chloro-2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

Analogously to Example 2, the corresponding imine is produced startingfrom 1.0 g of4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 492 mg of 5-aminoquinolin-2(1H)-one. 20 mg of the title compound isobtained by reaction of 300 mg of the imine with 3.2 ml of BBr₃ (1N indichloromethane).

¹H-NMR (300 MHz, DMSO): δ=1.46 (s, 3H), 1.58 (s, 3H), 1.95 (d, 1H), 2.05(d, 1H), 5.28 (d, 1H), 6.08 (s, 1H), 6.20 (d, 1H), 6.40 (d, 1H),6.50-6.66 (m, 3H), 6.77 (s, 1H), 7.24 (t, 1H), 7.35 (t, 1H), 8.19 (d,1H), 10.04 (bs, 1H), 11.57 (bs, 1H)

Example 385-{[2,5-Dihydroxy-4,4-dimethyl-6-fluoro-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

Analogously to Example 2, the corresponding imine is produced startingfrom 1.0 g of4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal(Example 3) and 520 mg of 5-aminoquinolin-2(1H)-one. 255 mg of the titlecompound is obtained by reaction of 300 mg of imine with 3.3 ml of BBr₃(1N in dichloromethane).

¹H-NMR (300 MHz, CD₃OD): δ=1.58 (s, 3H), 1.70 (s, 3H), 2.07 (d, 1H),2.15 (d, 1H), 5.13 (s, 1H), 6.51 (d, 1H), 6.60 (d, 1H), 6.68 (d, 1H),6.74-6.95 (m, 2H), 7.36 (t, 1H), 8.22 (d, 1H)

Examples 39 and 40(−)-5-{[2,5-Dihydroxy-4,4-dimethyl-6-fluoro-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-oneand(+)-5-{[2,5-Dihydroxy-4,4-dimethyl-6-fluoro-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-oneSeparation of(+/−)-5-{[2,5-Dihydroxy-4,4-dimethyl-6-fluoro-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10,vvv). The (−)-enantiomer: MS (EI): M⁺=436, [α]_(D)−23.6° °(c=1.0, CHCl₃)and the (+)-enantiomer: MS (EI): M⁺=436, [α]_(D)+25.0° °(c=1.0, CHCl₃)are thus obtained.

Example 415-{[4,4-Dimethyl-5-methoxy-7-methyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino1-quinolin-2(1H)-one, Diastereomer A4-(2-Methoxy-4-methylphenyl)-4-methyl-2-oxopentanoic acid ethyl ester

Analogously to Example 7,2-methoxy-4-methylbenzoic acid methyl ester isproduced from 30 g of 2,4-cresotic acid and 58.6 ml of methyl iodidewith 124.3 g of potassium carbonate in 643 ml of DMF. The ester isreacted by reaction with 141 ml of methylmagnesium chloride (3 M in THF)in 475 ml of THF to form 1-(2-methoxy-4-methylphenyl)-1-methylethanol. 5g of the product that is obtained is reacted with 6.4 g of2-(trimethylsilyloxy)-acrylic acid ethyl ester in 102 ml ofdichloromethane at −70° C. with 2.3 ml of tin tetrachloride to form 4.84g of the title compound.

¹H-NMR (300 MHz, CDCl₃): δ=1.44 (s, 6H), 2.31 (s, 3H), 3.38 (s, 2H),3.81 (s, 3H), 6.66 (s, 1H), 6.72 (d, 1H), 7.12 (d, 1H)

4-(2-Methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal

Analogously to Example 7, 4.84 g of4-(2-methoxy-4-methylphenyl)-4-methyl-2-oxopentanoic acid ethyl ester isreacted with 7 ml of trifluoromethyltrimethylsilane and 3 ml oftetrabutylammonium fluoride solution (1 M in THF) in 56 ml THF to form4.14 g of4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoicacid ethyl ester. The product is reduced with 856 mg of lithium aluminumhydride in 170 ml of diethyl ether to 3.58 g of4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol.The oxidation of the diol is carried out analogously to Example 7 underSwern conditions with 1.1 ml of oxalyl chloride, 2.1 ml of DMSO and 8.0ml of triethylamine to 3.01 g of the title compound.

¹H-NMR (300 MHz, CDCl₃): δ=1.38 (s, 3H), 1.43 (s, 3H), 2.18 (d, 1H),3.45 (d, 1H), 3.87 (s, 3H), 6.67 (s, 1H), 6.70 (d, 1H), 6.98 (d, 1H),8.92 (s, 1H)

5-{[4,4-Dimethyl-5-methoxy-7-methyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

Analogously to Example 2, the corresponding imine is produced startingfrom 280 mg of4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 156 mg of 5-aminoquinolin-2(1H)-one. The latter is stirred at roomtemperature with 93 mg of aluminum chloride for 2.5 hours. The batch isadded to saturated bicarbonate solution and extracted with ethylacetate. The organic phase is washed with water and brine, dried(Na₂SO₄) and concentrated by evaporation in a vacuum. Afterchromatography on silica gel (dichloromethane/2-propanol 0->5%), 24 mgof the title compound is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.50 (s, 3H), 1.62 (s, 3H), 2.04 (d, 1H),2.13 (d, 1H), 2.20 (s, 3H), 3.85 (s, 3H), 5.13 (s, 1H), 6.51 (d, 1H),6.62 (d, 1H), 6.70 (d, 1H), 6.75 (s, 1H), 6.78 (s, 1H), 7.39 (t, 1H),8.23 (d, 1H)

Example 425-{[4,4-Dimethyl-7-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal

16.8 g of 4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acidethyl ester (WO 00/32584) in 600 ml of diethyl ether is mixed inportions at 0° C. with 2.7 g of lithium aluminum hydride. After stirringfor 10 hours, it is added to saturated bicarbonate solution and filteredthrough diatomaceous earth. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is washed withwater and brine, dried (Na₂SO₄) and concentrated by evaporation. Afterchromatography on silica gel (hexane/ethyl acetate 0->10%), 6.7 g ofdiol and 2.65 g of the title compound are obtained.

The production of the title compound from the diol that is obtained iscarried out by reaction of 3.0 g of diol, 6.6 ml of triethylamine and6.5 g of sulfur trioxide-pyridine complex in 34 ml of DMSO at roomtemperature in 48 hours of reaction time. It is added to 0.5Nhydrochloric acid and extracted with ethyl acetate. The organic phase iswashed with water and brine, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. After chromatography on silica gel(hexane/ethyl acetate 0->15%), 2.7 g of the title compound is obtainedas a yellow oil.

¹H-NMR (300 MHz, CDCl₃), δ=1.38 (s, 3H), 1.46 (s, 3H), 2.19 (d, 1H),3.37 (d, 1H), 3.58 (s, 1H), 3.87 (s, 3H), 6.55-6.64 (m, 2H), 7.06 (dd,1H), 8.97 (s, 1H)

5-{[4,4-Dimethyl-7-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

Analogously to Example 41, the corresponding imine is produced startingfrom 500 mg of4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 260 mg of 5-aminoquinolin-2(1H)-one. 10 mg of the title compound isobtained by reaction of 220 mg of imine with 197 mg of aluminumchloride.

¹H-NMR (CD₃OD): δ=1.51 (s, 3H), 1.63 (s, 3H), 2.07 (d, 1H), 2.14 (d,1H), 5.15 (s, 1H), 6.53 (d, 1H), 6.58-6.77 (m, 4H), 7.40 (t, 1H), 8.23(d, 1H)

Example 43(+)-5-{[2,5-Dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

Analogously to Example 3, 5 mg of the title compound is obtained byreaction of 50 mg of(+)-5-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-oneand 0.22 ml of BBr₃ (1 M in dichloromethane).

¹H-NMR (300 MHz, CD₃OD): δ=1.57 (s, 3H), 1.69 (s, 3H), 2.06 (d, 1H),2.15 (d, 1H), 5.16 (s, 1H), 6.51 (d, 1H), 6.62 (d, 1H), 6.69 (d, 1H),6.71 (d, 1H), 6.82 (d, 1H), 6.95 (t, 1H), 7.37 (t, 1H), 8.23 (d, 1H)

Example 444-{[2-Hydroxy-4,4-dimethyl-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide

Analogously to Example 10, the corresponding imine is produced startingfrom 600 mg of4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and308 mg of 4-amino-phthalide (Bull. Soc. Sci. Bretagne 26, 1951, SpecialEdition 5, p. 7, 96). As in Example 2, 650 mg of the imine is reacted byreaction with 7.7 ml of BBr₃ (1 M in dichloromethane), and 165 mg of thetitle compound is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.30 (s, 3H), 1.46 (s, 3H), 1.93 (d, 1H),2.18 (d, 1H), 3.57 (s, 3H), 5.10 (d, 1H), 5.20 (d, 1H), 5.32 (d, 1H),5.55 (d, 1H), 5.81 (s, 1H), 6.80 (d, 1H), 7.03 (d, 1H), 7.04 (d, 1H),7.20 (d, 1H), 7.27 (t, 1H), 7.37 (t, 1H)

Example 457-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2.5-diol

Analogously to Example 2, the corresponding imine is produced startingfrom 410 mg of4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 168 mg of 4-aminoindazole. 98 mg of the title compound is obtainedby reaction of 200 mg of imine with 6.7 ml of BBr₃ (1N indichloromethane).

¹H-NMR (300 MHz, DMSO-d₆): δ=1.48 (s, 3H), 1.59 (s, 3H), 1.97 (d, 1H),2.07 (d, 1H), 5.27 (d, 1H), 5.95 (s, 1H), 6.21 (d, 1H), 6.31 (d, 1H),6.72 (s, 1H), 6.74 (d, 1H), 6.76 (s, 1H), 7.08 (t, 1H), 8.13 (s, 1H),9.94 (s, 1H), 12.83 (s, 1H)

Examples 46 and 47(−)-7-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol(+)-7-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diolSeparation of(+/−)-7-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with hexane/2-propanol (98:2,vvv). The (−)-enantiomer: MS (EI): M⁺=425/427, [α]_(D)−3.0° °(c=1.0,CHCl₃) and the (+)-enantiomer: MS (EI): M⁺=425/427, [α]_(D)+5.0°°(c=1.0, CHCl₃) are thus obtained.

Examples 48 and 497-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol7-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

Analogously to Example 2, the corresponding imine is produced startingfrom 1.8 g of4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 780 mg of 4-aminoindazole. By reaction of 300 mg of the imine with10.6 ml of BBr₃ (1N in dichloromethane), 13 mg of7-fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-olas fraction 1 and 30 mg of7-fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diolas fraction 2 are obtained.

Fraction 1: ¹H-NMR (300 MHz, CDCl₃): δ=1.48 (s, 3H), 1.62 (s, 3H), 2.05(d, 1H), 2.16 (d, 1H), 3.85 (s, 3H), 4.62 (d, 1H), 5.07 (d, 1H), 6.43(d, 1H), 6.55 (dd, 1H), 6.71 (dd, 1H), 6.92 (d, 1H), 7.27 (t, 1H), 8.01(s, 1H)

Fraction 2: ¹H-NMR (300 MHz, CDCl₃): δ=1.54 (s, 3H), 1.65 (s, 3H), 2.07(d, 1H), 2.17 (d, 1H), 4.62 (d, 1H), 5.07 (d, 1H), 6.37-6.47 (m, 2H),6.72 (dd, 1H), 6.94 (d, 1H), 7.28 (t, 1H), 8.02 (s, 1H)

Examples 50 and 51(−)-7-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol(+)-7-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diolSeparation of(+/−)-7-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with hexane/2-propanol (98:2,vvv). The (−)-enantiomer: MS (EI): M⁺=409, [α]_(D)−40.5° °(c=0.2, CHCl₃)and the (+)-enantiomer: MS (EI): M⁺=409 are thus obtained.

Examples 52 and 535-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol,Diastereomer A5-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol,Diastereomer B4-(2-Fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal

4.12 g of 4-(2-fluoro-4-methoxyphenyl)-4-methyl-2-oxo-pentanoic acidethyl ester in 140 ml of diethyl ether is mixed in portions at 0° C.with 666 mg of lithium aluminum hydride. After stirring for 10 hours, itis added to saturated bicarbonate solution and filtered throughdiatomaceous earth. The phases are separated, and the aqueous phase isextracted with ethyl acetate. The organic phase is washed with water andbrine, dried (Na₂SO₄) and concentrated by evaporation. Afterchromatography on silica gel (hexane/ethyl acetate 0->10%), 2.74 g ofdiol and 416 mg of the title compound are obtained.

The production of the title compound from the diol that is obtained iscarried out by reaction of 3.0 g of the diol, 6.6 ml of triethylamine,and 6.5 g of sulfur trioxide-pyridine complex in 34 ml of DMSO at roomtemperature in 48 hours of reaction time. It is added to 0.5Nhydrochloric acid and extracted with ethyl acetate. The organic phase iswashed with water and brine, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. After chromatography on silica gel(hexane/ethyl acetate 0->15%), 1.73 g of the title compound is obtainedas a yellow oil.

¹H-NMR (300 MHz, CDCl₃), δ=1.39 (s, 3H), 1.46 (s, 3H), 2.26 (d, 1H),3.09 (d, 1H), 3.63 (s, 1H), 3.78 (s, 3H), 6.52-6.65 (m, 2H), 7.03 (t,1H), 9.04 (s, 1H)

5-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol,Diastereomer A and5-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol,Diastereomer B:

Analogously to Example 2, the corresponding imine is produced startingfrom 1.7 g of4-(2-fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 736 mg of 4-aminoindazole. By reaction of 300 mg of imine with 10.6ml of BBr₃ (1N in dichloromethane), 12 mg of5-fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol,Diastereomer B as fraction 1 and 90 mg of5-fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol,diastereomer A as fraction 2 are obtained.

Fraction 1: ¹H-NMR (300 MHz, CDCl₃): δ=1.48 (s, 3H), 1.58 (s, 3H), 2.06(d, 1H), 2.23 (d, 1H), 4.95 (d, 1H), 5.11 (d, 1H), 6.37 (d, 1H), 6.48(dd, 1H), 6.64 (d, 1H), 6.75 (s, 1H), 7.25 (t, 1H), 7.48 (s, 1H)

Fraction 2: ¹H-NMR (300 MHz, CDCl₃): δ=1.48 (s, 3H), 1.58 (s, 3H), 2.05(d, 1H), 2.24 (d, 1H), 5.04 (d, 1H), 5.12 (d, 1H), 6.37 (d, 1H), 6.48(dd, 1H), 6.58 (dd, 1H), 6.78 (d, 1H), 7.24 (t, 1H), 7.29 (s, 1H)

Example 541-[(1H-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol,Diastereomer A

Analogously to Example 41, the corresponding imine is produced startingfrom 850 mg of4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and390 mg of 4-aminoindazole. 138 mg of the title compound is obtained byreaction of 500 mg of imine with 495 mg of aluminum chloride.

¹H-NMR (300 MHz, CDCl₃), δ=1.52 (s, 3H), 1.66 (s, 3H), 2.05 (d, 1H),2.16 (d, 1H), 3.85 (s, 3H), 4.57 (d, 1H), 5.23 (d, 1H), 6.48 (d, 1H),6.82 (d, 1H), 6.92 (d, 1H), 6.95 (d, 1H), 7.12 (t, 1H), 7.29 (t, 1H),7.97 (s, 1H)

Example 551-[(1H-Indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,23,4-tetrahydronaphthalen-2-ol,Diastereomer B

Analogously to Example 2, 300 mg of the imine that is obtained inExample 54 is reacted with 11 ml of BBr₃ (1N in dichloromethane) to form24 mg of the title compound.

¹H-NMR (300 MHz, CD₃OD), δ=1.42 (s, 3H), 1.55 (s, 3H), 2.08 (d, 1H),2.23 (d, 1H), 3.33 (s, 3H), 5.33 (s, 1H), 6.63 (d, 1H), 6.72 (d, 1H),6.88 (d, 1H), 7.06 (d, 1H), 7.20-7.31 (m, 2H), 8.17 (s, 1H)

Example 561-[(1H-Indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

100 mg of the compound of Example 54 is reacted analogously to Example 1with 3.7 ml of BBr₃ (1N in dichloromethane) to form 47 mg of the titlecompound.

¹H-NMR (300 MHz, CD₃OD), δ=1.40 (s, 3H), 1.54 (s, 3H), 2.10 (d, 1H),2.25 (d, 1H), 5.36 (s, 1H), 6.60 (d, 1H), 6.94 (d, 1H), 7.12 (t, 1H),7.18-7.33 (m, 3H), 8.20 (s, 1H)

Example 577-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

Analogously to Example 2, the corresponding imine is produced startingfrom 350 mg of4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and158 mg of 4-aminoindazole. By reaction of 50 mg of imine with 1.8 ml ofBBr₃ (1N in dichloromethane), 29 mg of the title compound is obtained.

¹H-NMR (300 MHz, CDCl₃), δ=1.41 (s, 3H), 1.54 (s, 3H), 2.10 (d, 1H),2.19 (d, 1H), 4.63 (d, 1H), 5.14 (d, 1H), 6.43 (d, 1H), 6.95 (d, 1H),7.23-7.37 (m, 4H), 8.03 (s, 1H)

Example 581-[(1-Methyl-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol4-Amino-1-methylindazole

6.5 g of 4-nitroindazole (Chem. Ber. (1904), 37, 2583), 1.9 ml of methyliodide and 14.4 g of cesium carbonate in 110 ml of DMF are stirred for 2hours at 0° C. and then for 12 hours at room temperature. It is added towater and extracted with ethyl acetate. The organic phase is washed withwater and brine, dried (Na₂SO₄) and concentrated by evaporation. Theresidue is recrystallized from ethyl acetate/hexane. 2.49 g of1-methyl-4-nitroindazole is obtained. The latter is hydrogenated in 70ml of THF with 420 mg of palladium on activated carbon under normalpressure with hydrogen. The batch is filtered through diatomaceous earthand completely concentrated by evaporation. 2.1 g of the title compoundis obtained.

¹H-NMR (300 MHz, CD₃OD), δ=3.96 (s, 3H), 6.35 (d, 1H), 6.75 (d, 1H),7.16 (d, 1H), 8.06 (s, 1H)

1-[(1-Methyl-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

Analogously to Example 3, the corresponding imine is produced startingfrom 296 mg of4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and150 mg of 4-amino-1-methylindazole. By reaction of 100 mg of the iminewith 0.5 ml of titanium tetrachloride, 100 mg of the title compound isobtained.

Melting point: 172-174° C.

Examples 59 and 607-Ethyl-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol7-Ethyl-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol2-Hydroxy-4-(4-iodo-2-methoxyphenyl)-4-methyl-2-trifluoromethylvalericacid methyl ester

3 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid (WO98/54159) is added in a solution of 1.3 ml of thionyl chloride in 12 mlof methanol at 0° C. and stirred for 10 hours at room temperature. It isadded to saturated bicarbonate solution and extracted with ethylacetate. The organic phase is washed with bicarbonate solution andbrine, dried (Na₂SO₄) and concentrated by evaporation. 3.2 g of4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid methyl ester isobtained as a crude product. This ester is mixed with 4.5 ml oftrifluoromethyltrimethylsilane in 70 ml of DMF and 1.63 g of cesiumcarbonate at 0° C. and stirred for 10 hours at room temperature. 20 mgof tetrabutylammonium fluoride is added, and it is stirred for another30 minutes at room temperature. The batch is added to water andextracted with ethyl acetate. The organic phase is washed with water andbrine, dried (Na₂SO₄) and concentrated by evaporation. Afterchromatography on silica gel (hexane/ethyl acetate 0->15%), 1.47 g ofthe title compound is obtained as a yellow oil.

¹H-NMR (300 MHz, CDCl₃), δ=1.34 (s, 3H), 1.42 (s, 3H), 2.30 (d, 1H),2.97 (d, 1H), 3.36 (s, 3H), 3.84 (s, 3H), 6.88 (dd, 1H), 7.13 (dd, 1H),7.23 (dd, 1H)

4-(4-Ethyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanal:1 g of2-hydroxy-4-(4-iodo-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-valericacid methyl ester, 860 mg of tributylvinyl tin, 103 mg ofpalladium-dibenzylidene acetone complex and 30 mg of triphenylphosphinein 17 ml of THF are refluxed under argon atmosphere for 57 hours. It isfiltered through diatomaceous earth and completely concentrated byevaporation. After chromatography on silica gel (hexane/ethyl acetate0->2%), 339 mg of2-hydroxy-4-(2-methoxy-4-vinylphenyl)-4-methyl-2-trifluoromethylvalericacid methyl ester is obtained. The latter is stirred with 56 mg oflithium aluminum hydride in 11 ml of diethyl ether at room temperaturefor 10 hours. It is added to saturated bicarbonate solution, filteredthrough diatomaceous earth and extracted with ethyl acetate. The organicphase is washed with bicarbonate solution and brine, dried (Na₂SO₄) andconcentrated by evaporation. After chromatography on silica gel(hexane/ethyl acetate 0->10%), 148 mg of2-hydroxy-4-(2-methoxy-4-vinylphenyl)-4-methyl-2-trifluoro-methylpentanolis obtained. The latter is hydrogenated in 4.3 ml of ethyl acetate with14 mg of palladium on activated carbon under normal pressure withhydrogen. The batch is filtered through diatomaceous earth andcompletely concentrated by evaporation. 127 mg of4-(4-ethyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanolis obtained. The diol that is obtained is reacted with 0.29 ml oftriethylamine and 280 mg of sulfur trioxide-pyridine complex in 1.3 mlof DMSO at room temperature in 10 hours of reaction time. It is added tosaturated ammonium chloride solution and extracted with ethyl acetate.The organic phase is washed with water and brine, dried (Na₂SO₄) andconcentrated by evaporation in a vacuum. After chromatography on silicagel (hexane/ethyl acetate 0->3%), 94 mg of the title compound isobtained as a colorless oil.

¹H-NMR (300 MHz, CDCl₃), δ=1.24 (t, 3H), 1.38 (s, 3H), 1.44 (s, 3H),2.17 (d, 1H), 2.62 (q, 2H), 3.46 (d, 1H), 3.88 (s, 3H), 6.68 (s, 1H),6.72 (d, 1H), 7.02 (d, 1H), 8.91 (s, 1H)

7-Ethyl-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-oland7-Ethyl-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

Analogously to Example 2, the corresponding imine is produced startingfrom 90 mg of4-(4-ethyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 38 mg of 4-aminoindazole. By reaction of 68 mg of imine with 0.39 mlof BBr₃ (1N in dichloromethane), 16 mg of7-ethyl-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-olas fraction 1 and 7 mg of7-ethyl-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-olas fraction 2 are obtained.

Fraction 1: ¹H-NMR (300 MHz, CDCl₃), δ=1.24 (t, 3H), 1.42 (s, 3H), 1.51(s, 3H), 2.03 (d, 1H), 2.14 (d, 1H), 2.63 (q, 2H), 3.18 (s, 3H), 3.74(bd, 1H), 5.33 (bd, 1H), 6.48 (s, 1H), 6.70 (d, 1H), 6.85 (s, 1H), 6.98(d, 1H), 7.32 (t, 2H), 7.89 (s, 1H)

Fraction 2: ¹H-NMR (300 MHz, CDCl₃), δ=1.00 (t, 3H), 1.55 (s, 3H), 1.65(s, 3H), 2.04 (d, 1H), 2.18 (d, 1H), 2.36 (q, 2H), 3.18 (s, 3H), 4.65(bd, 1H), 5.09 (bd, 1H), 6.47 (d, 1H), 6.48 (s, 1H), 6.76 (s, 1H), 6.92(d, 1H), 7.29 (t, 2H), 8.00 (s, 1H)

Example 611-[(1-Methyl-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

Analogously to Example 2, 163 mg of the imine that is describedaccording to Example 58 with 0.97 ml of BBr₃ (1N in dichloromethane) isreacted to form 44 mg of the title compound.

¹H-NMR (300 MHz, CD₃OD), δ=1.56 (s, 3H), 1.68 (s, 3H), 2.05 (d, 1H),2.14 (d, 1H), 4.02 (s, 3H), 5.15 (s, 1H), 6.34 (d, 1H), 6.67 (d, 1H),6.78 (d, 1H), 6.82-6.98 (m, 2H), 7.25 (t, 2H), 8.07 (s, 1H)

Examples 62 and 635-{[7-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one5-{[7-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino1-isoquinolin-1(2H)-one

Analogously to Example 2, the corresponding imine is produced startingfrom 385 mg of4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanaland 200 mg of 5-aminoisoquinolin-1(2H)-one. By reaction of 300 mg ofimine with 10.0 ml of BBr₃ (1N in dichloromethane), 10 mg of5-{[7-fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-[(2H)-oneas fraction 1 and 100 mg of5-{[7-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-oneas fraction 2 are obtained.

Fraction 1: ¹H-NMR (300 MHz, DMSO-d₆), δ=1.32 (s, 3H), 1.47 (s, 3H),1.95 (d, 1H), 2.24 (d, 1H), 3.44 (s, 3H), 5.01-5.14 (m, 2H), 5.85 (s,1H), 6.70 (dd, 1H), 6.78 (d, 1H), 6.86 (dd, 1H), 6.98 (dd, 1H), 7.22 (d,1H), 7.31 (t, 1H), 7.52 (d, 1H), 11.10 (bd, 1H)

Fraction 2: ¹H-NMR (300 MMHz, DMSO-d₆), δ=1.47 (s, 3H), 1.58 (s, 3H),1.97 (d, 1H), 2.08 (d, 1H), 5.30 (d, 1H), 5.94 (d, 1H), 6.13 (s, 1H),6.35 (dd, 1H), 6.54 (dd, 1H), 6.81 (d, 1H), 7.03 (d, 1H), 7.17 (dd, 1H),7.25 (t, 1H), 7.51 (d, 1H), 9.98 (bs, 1H), 11.25 (bd, 1H)

Examples 64 and 65(−)-5-{[7-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino1-isoquinolin-1(2H)-one(+)-5-{[7-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-oneSeparation of(+/−)-5-{[7-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10,vvv). The (−)-enantiomer: MS (EI): M⁺=436, [α]_(D)−62.5° °(c=0.5, CHCl₃)and the (+)-enantiomer: MS (EI): M⁺=436, [α]_(D+)75.6° °(c=0.8, CHCl₃)are thus obtained.

Example 665-{[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl]-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one,Diastereomer A 5-Amino-2-methyl-phthalazin-1-one3-Bromo-4-nitro-phthalide

5.37 g of 4-nitrophthalide (Tetrahedron Lett. (2001), 42, pp. 1647-50),8.04 g of N-bromosuccinimide and 196 mg of benzoyl peroxide are refluxedin 80 ml of benzotrifluoride and heated by exposure to light until thereaction is completed. It is added to water, extracted withdichloromethane, washed several times with water, dried, and the solventis removed in a vacuum. 7.24 g of 3-bromo-4-nitro-phthalide is obtainedas a solid.

¹H-NMR (300 MHz, CDCl₃), δ=7.26 (s, 1H), 7.88 (t, 1H), 8.3 (d, 1H), 8.56(d, 1H)

5-Nitro-phthalazin-1-one

18.25 g of hydrazine sulfate and 14.88 g of sodium carbonate are stirredin 300 ml of DMF at 100° C. for 1 hour. Then, 7.24 g of3-bromo-4-nitro-phthalide in 100 ml of DMF is added, and it is stirredfor another 4 hours at 100° C. It is added to water, extracted severaltimes with ethyl acetate, and the organic phase is washed with water andbrine. It is dried, and the solvent is removed in a vacuum. Afterrecrystallization from ethyl acetate, 2.35 g of 5-nitro-phthalazin-1-oneis obtained as a solid.

¹H-NMR (300 MHz, DMSO-d₆), δ=8.05 (t, 1H), 8.57-8.66 (m, 2H), 8.73 (s,1H), 13.13 (bs, 1H)

2-Methy-5-nitro-phthalazin-1-one

1.6 g of 5-nitro-phthalazin-1-one and 2.31 g of potassium carbonate arestirred for 10 minutes at room temperature in 60 ml of DMF. 1.1 ml ofmethyl iodide is added, and it is stirred overnight. It is added towater, extracted several times with ethyl acetate, and the organic phaseis washed with water and brine. It is dried, and the solvent is removedin a vacuum. 1.57 g of 2-methyl-5-nitro-phthalazin-1-one is obtained asa yellow solid.

¹H-NMR (300 MHz, DMSO-d₆), δ=3.73 (s, 3H), 8.05 (t, 1H), 8.62 (d, 2H),8.75 (s, 1H)

5-Amino-2-methyl-phthalazin-1-one

1.57 g of 2-methyl-5-nitro-phthalazin-1-one and 130 mg of palladium onactivated carbon are suspended in 45 ml of ethyl acetate andhydrogenated with hydrogen under normal pressure. It is filtered throughdiatomaceous earth, and the solvent is removed in a vacuum. 1.26 g of5-amino-2-methyl-phthalazin-1-one is obtained as a yellow solid.

¹H-NMR (300 MHz, CDCl₃), =3.81 (s, 3H), 7.0 (d, 1H), 7.5 (t, 1H), 7.8(d, 1H), 8.16 (s, 1H)

5-{[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one

Analogously to Example 10, the corresponding imine is produced startingfrom 200 mg of4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 114 mg of 5-amino-2-methyl-phthalazin-1-one. As in Example 3, 50 mgof imine is reacted by reaction with 0.23 ml of titanium tetrachloride,and 12 mg of the title compound is obtained.

Melting point: 262-263° C.

Example 675-{[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1(2H)-one5-Amino-phthalazin-1-one

980 mg of 5-nitro-phthalazin-1-one (Example 66) and 100 mg of palladiumon activated carbon are suspended in 50 ml of ethyl acetate and 1 ml oftriethylamine, and it is hydrogenated with hydrogen under normalpressure. It is filtered through diatomaceous earth, and the solvent isremoved in a vacuum. 830 g of 5-amino-phthalazin-1-one as a solid isobtained as a crude product.

¹H-NMR (300 MHz, DMSO-d₆), δ=6.26 (bs, 2H), 7.00 (d, 1H), 7.32 (d, 1H),7.44 (t, 1H), 8.48 (s, 1H), 12.35 (bs, 1H)

5-{[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1(2H)-one

Analogously to Example 10, the corresponding imine is produced startingfrom 200 mg of4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanaland 105 mg of 5-amino-phthalazin-1-one. As in Example 3, 50 mg of imineis reacted by reaction with 0.22 ml of titanium tetrachloride, and 36 mgof the title compound is obtained.

¹H-NMR (300 MHz, CD₃OD), δ=1.53 (s, 3H), 1.64 (s, 3H), 2.12 (s, 2H),3.94 (d, 3H), 5.24 (s, 1H), 6.96 (dd, 1H), 7.03 (dd, 1H), 7.24 (dd, 1H),7.58-7.65 (m, 2H), 8.55 (s, 1H)

Example 685-{[7-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one

Analogously to Example 10, the corresponding imine is produced startingfrom 200 mg of4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanaland 108 mg of 5-amino-2-methyl-phthalazin-1-one. As in Example 2, 225 mgof imine is reacted by reaction with 2.3 ml of BBr₃ (1 M indichloromethane), and 12 mg of the title compound is obtained.

¹H-NMR (300 MHz, CD₃OD), δ=1.55 (s, 3H), 1.66 (s, 3H), 2.08 (d, 1H),2.14 (d, 1H), 5.22 (s, 1H), 6.74 (s, 1H), 6.78 (s, 1H), 7.18-7.27 (m,1H), 7.62-7.72 (m, 2H), 8.57 (s, 1H)

Example 695-{[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one,Diastereomer B

Analogously to Example 10, the corresponding imine is produced startingfrom 200 mg of4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanaland 114 mg of 5-amino-2-methyl-phthalazin-1-one. As in Example 2, 112 mgof imine is reacted by reaction with 0.36 ml of BBr₃ (1 M indichloromethane), and 38 mg of the title compound is obtained.

¹H-NMR (300 MHz, CDCl₃), δ=1.53 (s, 3H), 1.64 (s, 3H), 2.11 (d, 1H),3.85 (s, 3H), 3.97 (d, 3H), 5.02 (d, 1H), 5.13 (d, 1H), 6.97 (d, 1H),7.00 (dd, 1H), 7.08 (d, 1H), 7.61 (t, 1H), 7.83 (d, 1H), 8.15 (s, 1H)

Example 705-{[6-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one

29 mg of the compound of Example 69 is reacted analogously to Example 1with 0.13 ml of BBr₃ (1N in dichloromethane) to form 18 mg of the titlecompound.

¹H-NMR (300 MHz, CD₃OD), δ=1.60 (s, 3H), 1.71 (s, 3H), 2.09 (d, 1H),2.16 (d, 1H), 3.83 (s, 3H), 5.23 (s, 1H), 6.79 (dd, 1H), 6.90 (dd, 1H),7.22 (dd, 1H), 7.59-7.68 (m, 2H), 8.56 (s, 1H)

Example 715-{[6-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1(2H)-one

80 mg of the compound of Example 67 is reacted analogously to Example 1with 0.35 ml of BBr₃ (1N in dichloromethane) to form 15 mg of the titlecompound.

¹H-NMR (300 MHz, CD₃OD), δ=1.60 (s, 3H), 1.71 (s, 3H), 2.14 (d, 2H),5.23 (s, 1H), 6.80 (dd, 1H), 6.90 (dd, 1H), 7.25 (dd, 1H), 7.58-7.68 (m,2H), 8.56 (s, 1H)

Examples 72 and 735-{[2-Hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino1-phthalazin-1(2H)-one5-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1(2H)-one

Analogously to Example 10, the corresponding imine is produced startingfrom 500 mg of4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and277 mg of 5-amino-phthalazin-1-one. As in Example 2, 32 mg of5-{[2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-[(2H)-oneas fraction 1 and 35 mg of5-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1(2H)-oneas fraction 3 are obtained by reaction of 470 mg of imine with 5.4 ml ofBBr₃ (1 M in dichloromethane).

Fraction 1: ¹H-NMR (300 MHz, DMSO-d₆), δ=1.32 (s, 3H), 1.50 (s, 3H),1.96 (d, 1H), 2.23 (d, 1H), 3.47 (s, 3H), 5.17 (d, 1H), 5.93 (s, 1H),6.06 (d, 1H), 6.78 (d, 1H), 7.04 (d, 1H), 7.27 (t, 1H), 7.37 (d, 1H),7.44 (d, 1H), 7.62 (t, 1H), 8.67 (s, 1H), 12.39 (s, 1H)

Fraction 3: ¹H-NMR (300 MHz, CD₃OD), δ=1.57 (s, 3H), 1.69 (s, 3H), 2.07(d, 1H), 2.15 (d, 1H), 5.24 (s, 1H), 6.72 (d, 1H), 6.81 (d, 1H), 6.96(t, 1H), 7.24 (dd, 1H), 7.57-7.70 (m, 2H), 8.57 (s, 1H)

Examples 74, 75 and 765-{[2-Hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one5-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one,Diastereomer A5-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one,Diastereomer B

Analogously to Example 10, the corresponding imine is produced startingfrom 500 mg of4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and302 mg of 5-amino-2-methylphthalazin-1-one. As in Example 2, 158 mg of5-{[2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-oneas fraction 1, 66 mg of5-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one,diastereomer A as fraction 4, and 77 mg of5-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one,diastereomer A as fraction 5 are obtained by reaction of 570 mg of iminewith 6.4 ml of BBr₃ (1 M in dichloromethane).

Fraction 1: ¹H-NMR (300 MHz, CD₃OD), δ=1.42 (s, 3H), 1.58 (s, 3H), 2.08(d, 1H), 2.26 (d, 1H), 3.47 (s, 3H), 3.77 (s, 3H), 5.33 (s, 1H), 6.76(d, 1H), 7.07 (d, 1H), 7.29 (t, 1H), 7.52 (dd, 1H), 7.60-7.71 (m, 2H),8.51 (s, 1H)

Fraction 4: ¹H-NMR (300 MHz, CD₃OD), δ=1.42 (s, 3H), 1.56 (s, 3H), 2.09(d, 1H), 2.27 (d, 1H), 3.78 (s, 3H), 5.33 (s, 1H), 6.62 (d, 1H), 6.95(d, 1H), 7.14 (t, 1H), 7.56 (dd, 1H), 7.59-7.70 (m, 2H), 8.54 (s, 1H)

Fraction 5: ¹H-NMR (300 MHz, CD₃OD), δ=1.57 (s, 3H), 1.68 (s, 3H), 2.07(d, 1H), 2.14 (d, 1H), 3.77 (s, 3H), 5.33 (s, 1H), 6.71 (d, 1H), 6.80(d, 1H), 6.96 (t, 1H), 7.22 (dd, 1H), 7.58-7.69 (m, 2H), 8.56 (s, 1H)

Examples 77 and 78(−)-5-{[2-Hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one(+)-5-{[2-Hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-oneSeparation of(+/−)-5-{[2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10,vvv). The (−)-enantiomer: MS (EI): M⁺=447, [α]_(D)−48.0° °(c=0.7, CHCl₃)and the (+)-enantiomer: MS (EI): M⁺=447, [α]_(D)+45.6° °(c=0.8, CHCl₃)are thus obtained.

Examples 79 and 80(−)-5-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-12,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one,Diastereomer A(+)-5-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one,Diastereomer A Separation of(+/−)-5-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one,diastereomer A

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (85:15,vvv). The (−)-enantiomer: MS (EI): M⁺=433, [α]_(D)−25.3° (c=1.0, CHCl₃)and the (+)-enantiomer: MS (EI): M⁺=433 are thus obtained.

Examples 81 and 82(−)-5-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one,Diastereomer A(+)-5-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1.2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one,Diastereomer A Separation of(+/−)-5-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one,diastereomer B

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10,vvv). The (−)-enantiomer: MS (EI): M⁺=433, [α]_(D)−10.1° °(c=0.8, CHCl₃)and the (+)-enantiomer: MS (EI): M⁺=433, [α]_(D+)5.8° °(c=0.9, CHCl₃)are thus obtained.

Example 83cis-1-[(2-Methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol(Markus Berger) 5-Amino-2-methylquinazoline

12.7 g (62 mmol) of 2-methyl-5-nitro-3H-quinazolin-4-one (M. T. Bogert,V. J. Chambers J. Org Chem. 1905, 649-658) and 37.5 g of phosphoruspentachloride are refluxed in 75 ml of phosphoryl chloride over 20hours. After cooling, it is poured into saturated NaHCO₃ solution andextracted with ethyl acetate. The organic phase is dried, and thesolvent is removed. 14 g of 4-chloro-2-methyl-5-nitroquinazoline, ofwhich 4.5 g (20.2 mmol) in 225 ml of ethyl acetate and 22.5 ml oftriethylamine are dissolved, is obtained. 2 g of palladium is added tocarbon, and it is stirred while being cooled with ice for 4 hours underhydrogen atmosphere at normal pressure. Catalyst is removed from thesolution by means of filtration through Celite, whereby it is rewashedwith 200 ml of ethanol and concentrated by evaporation. Afterchromatography on silica gel with ethyl acetate-ethanol (0-10%), 530 mgof the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=2.87 (s, 3H), 4.52 (br., 2H), 6.77 (d, 1H),7.33 (d, 1H), 7.65 (t, 1H), 9.40 (s, 1H).

(rac)-1,1,1,-Trifluoro-4-phenyl-2-[(E/Z)-(2-methyl-quinazol-5-yl)iminomethyl]-4-methyl-pentan-2-ol

0.3 ml of titanium tetraethylate is added to 140 mg (0.54 mmol) of2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)-pentanal and 100 mg(0.63 mmol) of 5-amino-2-methylquinazoline in 15 ml of toluene, and themixture is heated for over 2 hours to 100° C. After cooling, it ispoured into water, and vigorous stirring is continued. The suspension isfiltered through Celite, and it is rewashed thoroughly with ethylacetate. The phases of the filtrate are separated, and it is extractedagain with ethyl acetate. It is dried on sodium sulfate, and the solventis removed in a vacuum. After chromatographic purification on silica gel(hexane/ethyl acetate 0-60%), 123 mg of(rac)-1,1,1,-trifluoro-4-phenyl-2-[(E/Z)-(2-methyl-quinazol-5-yl)iminomethyl]-4-methyl-pentan-2-olis obtained.

cis-1-[(2-Methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

82 mg (0.20 mmol) of imine is taken up in 7 ml of dichloromethane andcooled to −70° C. 0.8 ml (0.8 mmol) of a 1 M titanium tetrachloridesolution in dichloromethane is added in drops over 10 minutes, and it isstirred for another 6 hours at −65° C. The solution is poured into asaturated sodium bicarbonate solution and stirred vigorously for 5minutes. It is extracted with dichloromethane, washed with saturatedsodium chloride solution and dried on sodium sulfate. Afterconcentration by evaporation and chromatography on silica gel(hexane/ethyl acetate 0-65%), 46 mg of the desired product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.46 (s, 3H), 1.63 (s, 3H), 2.19 (d, 1H),2.29 (d, 1H), 2.87 (s, 3H), 5.14 (d, 1H), 5.97 (d, 1H), 6.81 (d, 1H),7.15 (t, 1H), 7.36-7.43 (m, 2H), 7.42 (d, 1H), 7.75 (t, 1H), 9.42 (s,1H).

Example 84trans-5-Methoxy-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The compound was produced analogously to Example 83.

¹H-NMR (300 MHz, CDCl₃): δ=1.43 (s, 3H), 1.54 (s, 3H), 2.07 (d, 1H),2.18 (d, 1H), 2.84 (s, 3H), 3.21 (s, 3H), 4.31 (d, 1H), 5.38 (d, 1H),6.63 (d, 1H), 7.05 (d, 1H), 7.18 (d, 1H), 7.31 (t, 1H), 7.43 (d, 1H),7.81 (t, 1H), 9.13 (s, 1H).

Example 85cis-6-Chloro-5-methoxy-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The compound was produced analogously to Example 83.

¹H-NMR (300 MHz, CDCl₃): δ=1.58 (s, 3H), 1.74 (s, 3H), 2.14 (d, 1H),2.25 (d, 1H), 2.88 (s, 3H), 3.97 (s, 3H), 5.05 (d, 1H), 5.92 (d, 1H),6.79 (d, 1H), 7.09 (d, 1H), 7.19 (d, 1H), 7.30 (d, 1H), 7.75 (t, 1H),9.39 (s, 1H).

Example 86cis-6-Fluoro-5-methoxy-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The compound was produced analogously to Example 83.

¹H-NMR (CDCl₃): δ=1.57 (s, 3H), 1.74 (s, 3H), 2.13 (d, 1H), 2.26 (d,1H), 2.88 (s, 3H), 3.97 (s, 3H), 5.02 (d, 1H), 5.85 (d, 1H), 6.79 (d,1H), 6.93 (dd, 1H), 7.07 (dd, 1H), 7.29 (d, 1H), 7.74 (d, 1H), 9.33 (s,1H).

Example 87cis-6-[(2-Methylquinazolin-5-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1,3-dioxol-7-ol

The compound is synthesized as described in Example 83.

¹H-NMR (300 MHz, CDCl₃): δ=1.52 (s, 3H), 1.66 (s, 3H), 2.10 (d, 1H),2.26 (d, 1H), 2.88 (s, 3H), 5.04 (d, 1H), 5.94 (d, 1H), 5.99 (d, 2H),6.65 (d, 1H), 6.80 (d, 1H), 6.86 (d, 1H), 7.76 (t, 1H), 9.52 (s, 1H).

Example 88cis-6-Chloro-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

The compound is produced by ether cleavage as described in Example 3.

¹H-NMR (300 MHz, CDCl₃): δ=1.54 (s, 3H), 1.68 (s, 3H), 2.06 (d, 1H),2.20 (d, 1H), 2.81 (s, 3H), 4.98 (d, 1H), 5.81 (d, 1H), 5.91 (br., 1H),6.73 (d, 1H), 6.86 (d, 1H), 7.08 (d, 1H), 7.23 (d, 1H), 9.35 (s, 11H).

Example 89cis-6-Fluoro-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

The compound is produced by ether cleavage as described in Example 3.

¹H-NMR (300 MHz, CDCl₃): δ=1.62 (s, 3H), 1.77 (s, 3H), 2.13 (d, 1H),2.27 (d, 1H), 2.88 (s, 3H), 5.03 (d, 1H), 5.67 (br, 1H), 5.78 (d, 1H),6.79 (d, 1H), 6.91 (d, 2H), 7.29 (d, 1H), 7.73 (t, 1H), 9.35 (s, 1H).

Example 90cis-6-[(7-Fluoro-2-methylquinazolin-5-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1,3-dioxol-7-ol5-Amino-7-fluoro-2-methyquinazoline

17 g (70.5 mmol) of 3,6-difluoro-2-N-pivaloylaminobenzaldehyde (L.Florvall, I. Fagervall, L.-G- Larsson, S. B. Ross, Eur. J. Med. Chem. 34(1999) 137-151), 9.2 g of acetamidine hydrochloride, 13.4 g of potassiumcarbonate and 10.4 g of molecular sieve (4A) are combined in 70 ml ofbutyronitrile. It is heated while being stirred vigorously for 17 hoursto 145° C., and the solvent is removed in a vacuum. After the residue ischromatographed on silica gel with hexane/ethyl acetate (0-70%), 4.5 gof 7-fluoro-5-N-pivaloylamino-2-methyquinazoline is obtained.

1 g (3.82 mmol) of 7-fluoro-5-N-pivaloylamino-2-methyquinazoline isdissolved in 74 ml of toluene and cooled to −70° C. 9.5 ml (11.4 mmol)of a 1.2 M diisobutylaluminum hydride solution in toluene is added indrops over 30 minutes. The reaction mixture is allowed to heat to −40°C. and stirred for 4 hours at −40° C. Water is slowly added, and it isstirred for 30 minutes at room temperature until a precipitate is formedthat is removed by means of filtration through Celite. The phases areseparated, washed with saturated sodium chloride solution and dried onsodium sulfate. After chromatography on silica gel with hexane-ethylacetate (0-100%), 64 mg of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=2.83 (s, 3H), 4.67 (br., 2H), 6.50 (dd, 1H),6.93 (dd, 1H), 9.23 (s, 1H).

0.1 ml of titanium tetraethylate is added to 60 mg (0.46 mmol) of rac.4-(1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanaland 32 mg (0.18 mmol) of 5-amino-7-fluoro-2-methylquinazoline in 7 ml oftoluene, and the mixture is heated over 2.5 hours to 100° C. Aftercooling, it is poured into water, and vigorous stirring is continued.The suspension is filtered through Celite, and it is thoroughly rewashedwith ethyl acetate. The phases of the filtrate are separated, and it isextracted again with ethyl acetate. It is dried on sodium sulfate, andthe solvent is removed in a vacuum. The4-(1,3-benzodioxol-4-yl)-1,1,1-trifluoro-2-[(E/Z)-(7-fluoro-2-methylquinazolin-5-yl)iminomethyl]-4-methyl-pentan-2-olthat is thus obtained in crude form is taken up in 8 ml ofdichloromethane and cooled to −70° C. 1.1 ml (1.1 mmol) of a 1 Mtitanium tetrachloride solution in dichloromethane is added in dropsover 10 minutes, and it is stirred for another hour at −70° C. Thesolution is poured into a saturated sodium bicarbonate solution andvigorously stirred for 5 minutes. It is extracted with dichloromethane,washed with saturated sodium chloride solution and dried on sodiumsulfate. After concentration by evaporation and chromatography on silicagel (hexane/ethyl acetate 0-75%), 26 mg of the desired product isobtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.53 (s, 3H), 1.66 (s, 3H), 2.12 (d, 1H),2.27 (d, 1H), 2.84 (s, 3H), 4.94 (d, 1H), 5.99 (s, 1H), 6.00 (s, 1H),6.02 (d, 1H), 6.50 (dd, 1H), 6.68 (d, 1H), 6.83 (d, 1H), 6.89 (dd, 1H),9.26 (s, 1H).

Example 91trans-5-Methoxy-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The compound was produced analogously to Example 83.

¹H-NMR (300 MHz, CDCl₃): δ=1.42 (s, 3H), 1.55 (s, 3H), 2.07 (d, 1H),2.17 (d, 1H), 2.80 (s, 3H), 3.33 (s, 3H), 4.57 (d, 1H), 5.31 (d, 1H),6.66 (d, 1H), 6.88 (dd, 1H), 7.00 (dd, 1H), 7.05 (d, 1H), 7.30 (t, 1H),9.03 (s, 1H).

Example 92cis-6-Chloro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

The compound is produced by ether cleavage as described in Example 3.

¹H-NMR (300 MHz, CDCl₃): δ=1.60 (s, 3H), 1.73 (s, 3H), 2.12 (d, 1H),2.24 (d, 1H), 2.84 (s, 3H), 4.96 (d, 1H), 5.98 (d, 1H), 6.01 (s, 1H),6.51 (dd, 1H), 6.88 (d, 1H), 6.91 (dd, 1H), 7.17 (d, 1H), 9.23 (s, 1H).

Example 93cis-6-Fluoro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

The compound is produced by ether cleavage as described in Example 3.

¹H-NMR (300 MHz, CD₃OD): δ=1.61 (s, 3H), 1.72 (s, 3H), 2.15 (m, 2H),2.78 (s, 3H), 5.30 (s, 1H), 6.72-6.82 (m, 3H), 6.92 (dd, 1H), 9.55 (s,1H).

Example 94trans-7-Fluoro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, CD₃OD): δ=1.40 (s, 3H), 1.53 (s, 3H), 2.07 (d, 1H),2.18 (d, 1H), 2.81 (s, 3H), 3.34 (s, 3H), 4.52 (d, 1H), 5.25 (d, 1H),6.41 (dd, 1H), 6.74 (dd, 1H), 6.86 (dd, 1H), 7.01 (dd, 1H), 9.03 (s,1H).

Example 95cis-6-Chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol5-Amino-8-fluoro-2-methylquinazoline

A solution of 2.4 g (18.6 mmol) of 2,5-difluoroaniline in 11 ml of waterand 1.6 ml of concentrated hydrochloric acid (37%) that is 50° C. isadded to a solution of 3.35 g (20.25 mmol) of chloral hydrate and 21.27g (149.7 mmol) of sodium sulfate in 72 ml of water, which was previouslystirred at this temperature for 1 hour. It is stirred for another 30minutes at room temperature, and after 4.09 g (58.9 mmol) ofhydroxylammonium chloride in 19 ml of water is added, it is heated for45 minutes to 125° C. and kept at this temperature for 5 minutes. Aftercooling and after another hour, the deposited light-brown precipitate isfiltered off, washed with water and dried. 3.0 g (15.0 mmol) of thehydroxylimine is obtained as an intermediate product, which is dissolvedin portions in 15 ml of concentrated sulfuric acid at 60° C. After theaddition is completed, it is heated for 2 hours to 80° C. and for 4hours to 90° C. It is allowed to cool off, and the solution is pouredinto 100 g of ice. It is extracted with ethyl acetate, the organic phaseis washed with water, dried on sodium sulfate, and concentrated byevaporation. After chromatography on silica gel with hexane-ethylacetate (0-45%), 1.2 g (7.1 mmol) of 4,7-difluorisatin is obtained. 1.8ml of a 30% hydrogen peroxide solution is added in drops to isatin in 30ml of a 1 molar sodium hydroxide solution over 10 minutes. After 2 hoursof stirring at room temperature, it is cooled to 0° C., and 5 ml of a 4molar hydrochloric acid is added and diluted with 50 ml of water. It isextracted with ethyl acetate, dried on sodium sulfate, concentrated byevaporation, and 1.27 g of 3,6-difluoroanthranilic acid, which isreacted without further purification, is thus quantitatively obtained.

The 3,6-difluoroanthranilic acid is heated in 8 ml of acetic acidanhydride for 45 minutes to 100° C. After cooling, the acetic acid thatis produced and excess acetic acid anhydride are removed azeotropicallywith toluene in a vacuum. The residue is mixed with 40 ml of a 25%ammonia solution while being cooled with ice, and it is stirred for 72hours. It is diluted with water and acidified with acetic acid. It isextracted with ethyl acetate, the organic phase is washed with water,dried on sodium sulfate and concentrated by evaporation. The thusobtained 1.03 g (5.25 mmol) of 5,8-difluoro-2-methyl-3H-quinazolin-4-oneand 6 g of phosphorus pentachloride are heated in 20 ml of phosphorylchloride over 12 hours to 125° C. After cooling, it is poured intosaturated NaHCO₃ solution and extracted with ethyl acetate. The organicphase is dried, and the solvent is removed. 1.7 g of4-chloro-5,8-difluoro-2-methylquinazoline, which is dissolved in 60 mlof ethyl acetate and 5 ml of triethylamine, is obtained quantitatively.600 mg of palladium on carbon is added and shaken for 2 hours (480 ml ofhydrogen absorption) under hydrogen atmosphere at normal pressure.Catalyst is removed from the solution by means of filtration overCelite, whereby it is rewashed with 100 ml of ethanol and concentratedby evaporation. After chromatography on silica gel with hexane-ethylacetate-ethanol (0-40%), 550 mg of 5,8-difluoro-2-methylquinazoline isobtained. 890 mg (13.7 mmol) of sodium azide is added to 240 mg (1.3mmol) of 5,8-difluoro-2-methylquinazoline, 300 mg (1.13 mmol) of18-crown-6 in 10 ml of DMF, and the mixture is heated over 8 hours to125° C. The solvent is removed in a vacuum, and it is chromatographed onsilica gel with ethyl acetate, and 52 mg of product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=2.92 (s, 3H), 4.31 (br., 2H), 6.67 (dd, 1H),7.38 (dd, 1H), 9.37 (s, 1H). 0.23 ml (1.1 mmol) of titaniumtetraethylate is added to 140 mg (0.46 mmol) of4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanaland 100 mg (0.56 mmol) of 5-amino-8-fluoro-2-methylquinazoline in 14 mlof toluene, and the mixture is heated over 2 hours to 100° C. Aftercooling, it is poured into water, and vigorous stirring is continued.The suspension is filtered through Celite, and it is thoroughly rewashedwith ethyl acetate. The phases of the filtrate are separated, and it isextracted again with ethyl acetate. It is dried on sodium sulfate, andthe solvent is removed in a vacuum. The4-(3-chloro-2-methoxyphenyl)-1,1,1-trifluoro-2-[(E/Z)-(8-fluoro-2-methylquinazolin-5-yl)iminomethyl]-4-methyl-pentan-2-olthat is thus obtained in crude form is taken up in 23 ml ofdichloromethane and cooled to −30° C. 7.8 ml (7.8 mmol) of a 1 M borontribromide solution in dichloromethane is added in drops over 10minutes, allowed to come to room temperature over 1 hour, and stirredfor another 16 hours. The solution is poured into a mixture of ice andsaturated sodium bicarbonate solution and vigorously stirred for 15minutes. It is extracted with dichloromethane, washed with saturatedsodium chloride solution and dried on sodium sulfate. Afterconcentration by evaporation and chromatography on silica gel(hexane/ethyl acetate 0-50%), 64 mg of the desired product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.60 (s, 3H), 1.74 (s, 3H), 2.07 (d, 1H),2.26 (d, 1H), 2.93 (s, 3H), 4.99 (d, 1H), 5.66 (d, 1H), 5.99 (br., 1H),6.67 (dd, 1H), 6.91 (d, 1H), 7.16 (d, 1H), 7.49 (dd, 1H), 9.41 (s, 1H).

Example 96cis-1-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.45 (s, 3H), 1.61 (s, 3H), 2.17 (d, 1H),2.26 (d, 1H), 2.92 (s, 3H), 5.08 (d, 1H), 5.69 (d, 1H), 6.69 (dd, 1H),7.16 (t, 1H), 7.35 (m, 2H), 7.42 (d, 1H), 7.49 (t, 1H), 9.44 (s, 1H).

Example 97trans-8-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.50 (s, 3H), 1.63 (s, 3H), 2.14 (s, 2H),2.89 (s, 3H), 3.21 (s, 3H), 4.25 (d, 1H), 5.21 (d, 1H), 6.59 (dd, 1H),6.98 (dd, 1H), 7.04 (dd, 1H), 7.52 (dd, 1H), 9.21 (s, 1H).

Example 98cis-7-Chloro-1-[(−8-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.44 (s, 3H), 1.60 (s, 3H), 2.18 (d, 1H),2.27 (d, 1H), 2.93 (s, 3H), 5.00 (d, 1H), 5.71 (d, 1H), 6.66 (dd, 1H),7.28-7.37 (m, 3H), 7.50 (dd, 1H), 9.39 (s, 1H).

Example 99cis-6-Chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.57 (s, 3H), 1.72 (s, 3H), 2.12 (d, 1H),2.22 (d, 1H), 2.93 (s, 3H), 3.97 (s, 3H), 4.99 (d, 1H), 5.65 (d, 1H),6.67 (dd, 1H), 7.07 (d, 1H), 7.21 (d, 1H), 7.49 (dd, 1H), 9.39 (s, 1H).

Example 100cis-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.56 (s, 3H), 1.71 (s, 3H), 2.11 (d, 1H),2.22 (d, 1H), 2.93 (s, 3H), 3.97 (s, 3H), 4.97 (d, 1H), 5.60 (d, 1H),6.67 (dd, 1H), 6.93 (dd, 1H), 7.06 (dd, 1H), 7.48 (dd, 1H), 9.37 (s,1H).

Example 101cis-6-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1,3-dioxol-7-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.52 (s, 3H), 1.67 (s, 3H), 2.10 (d, 1H),2.27 (d, 1H), 2.94 (s, 3H), 4.96 (d, 1H), 5.67 (d, 1H), 5.99 (s, 1H),6.01 (s, 1H), 6.67 (d, 1H), 6.68 (dd, 1H), 6.86 (d, 1H), 7.49 (dd, 1H),9.44 (s, 1H).

Example 102cis-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CD₃OD): δ=1.60 (s, 3H), 1.72 (s, 3H), 2.09 (d, 1H),2.17 (d, 1H), 2.86 (s, 3H), 5.23 (s, 1H), 6.80-6.93 (m, 3H), 7.57 (dd,1H), 9.66 (s, 1H).

Example 103cis-6-[(2-Methylquinolin-5-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1,3-dioxol-7-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.50 (s, 3H), 1.60 (s, 3H), 2.08 (d, 1H),2.20 (d, 1H), 2.73 (s, 3H), 4.85 (d, 1H), 5.09 (d, 1H), 5.98 (s, 1H),5.99 (s, 1H), 6.62 (d, 1H), 6.81 (m, 2H), 7.22 (d, 1H), 7.50 (d, 1H),7.56 (t, 1H), 8.09 (d, 1H).

Example 104cis-6-[(2-Methyl-1,7-naphthyridin-5-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1,3-dioxol-7-ol

¹H-NMR (300 MHz, CD₃OD): δ=1.48 (s, 3H), 1.57 (s, 3H), 2.02 (d, 1H),2.17 (d, 1H), 2.76 (s, 3H), 5.06 (s, 1H), 5.96 (s, 2H), 6.61 (d, 1H),6.82 (d, 1H), 7.50 (d, 1H), 7.90 (s, 1H), 8.33 (d, 1H), 8.69 (s, 1H)

Example 105Rac.-5,8-Difluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol(Diastereomer B)

Melting point: 209-21 1° C.

Example 106Rac.-5-Fluoro-1-[(2-methylquinazolin-5-yl)amino]-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-diol(Diastereomer B)

Melting point: 11 5° C.

Example 107Rac.-5-Fluoro-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol(Diastereomer B)

¹H-NMR (300 MHz, CD₃OD): δ=1.51 (s, 3H), 1.66 (s, 3H), 2.08 (d, J=14 Hz,1H), 2.18 (d, J=14 Hz, 1H), 2.82 (s, 3H), 5.21 (s, 1H), 6.71-6.93 (m,3H), 7.19 (d, J=8 Hz, 1H), 7.77 (dd, J=9 Hz/8 Hz, 1H), 9.57 (s, 1H).)

Example 108Rac.-5-Fluoro-1-[(2-methylquinazolin-5-yl)amino]-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-diol(Diastereomer A)

MS (ESI): 4590 (M+1)

Example 1096-Fluoro-1-{[(2-hydroxymethyl)-quinolin-5-yl)aminol]}-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol5-[4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]-quinoline-2-carboxylicacid methyl ester

A solution that consists of4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoro-methylpentanal(872 mg, 2.84 mmol) and 5-aminoquinoline-2-carboxylic acid methyl ester(570 mg, 2.84 mmol) in 5.0 ml of concentrated acetic acid is allowed tostir for two days at room temperature. After repeated co-evaporationwith toluene, the residue is purified on silica gel with hexane/ethylacetate (0-100% ethyl acetate). 820 mg (59% of theory) of the product isobtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.41 (s, 3H), 1.59 (s, 3H), 2.35 (d, 1H),3.33 (d, 1H), 4.00 (d, 3H), 4.11 (s, 3H), 4.76 (s, 1H), 6.32-6.39 (m,1H), 6.49-6.56 (m, 1H), 6.66 (d, 1H), 6.81 (d, 1H), 7.60-7.65 (m, 2H),8.14-8.24 (m, 2H), 8.52 (d, 1H).

5-(6-Fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-ylamino)-quinoline-2-carboxylicacid methyl ester

5-[4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]-quinoline-2-carboxylicacid methyl ester (120 mg, 0.243 mmol) is dissolved in 2.0 ml ofdichloromethane. Titanium tetrachloride (1 M solution indichloromethane, 0.73 ml, 0.73 mmol) is added in drops within 15 minutesat −30° C. Then, the reaction mixture is allowed to stir for 3 hours at−30° C. to −1 5° C. By adding saturated sodium bicarbonate solution at−30° C., the reaction is brought to a halt. It is extracted with ethylacetate, the combined organic phases are washed with water and saturatedsodium chloride solution. After drying on sodium sulfate and after thesolvent is removed in a vacuum as well as subsequent purification onsilica gel with dichloromethane/methanol (0-3% methanol), 70 mg (58% oftheory) of the product is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.56 (s, 3H), 1.68 (s, 3H), 2.16 (s, 2H),3.96 (d, 3H), 4.08 (s, 3H), 5.28 (s, 1H), 6.91-6.99 (m, 2H), 7.03-7.09(m, 1H), 7.57 (d, 1H), 7.68 (t, 1H), 8.12 (d, 1H), 8.72 (d, 1H).

6-Fluoro-1-{[(2-hydroxymethyl)-quinolin-5-yl)amino]}-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

5-(6-Fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinoline-2-carboxylicacid methyl ester (70 mg, 0.14 mmol) is dissolved in 5.0 ml of methanoland mixed with sodium borohydride (22 mg, 0.57 mmol). After one hour andafter 2 hours, in each case the same amounts are added to sodiumborohydride (total amounts: 66 mg, 0.171 mmol). By adding water, thereaction is brought to a halt. It is extracted with ethyl acetate, thecombined organic phases are washed with saturated sodium chloridesolution and dried on sodium sulfate. After the solvent is removed in avacuum, the purification of the residue on silica gel is carried outwith hexane/ethyl acetate (0-100% ethyl acetate). 21 mg (32% of theory)of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.48 (s, 3H), 1.61 (s, 3H), 2.01 (d, 1H),2.14 (d, 1H), 3.88 (d, 3H), 4.70 (d, 2H), 5.40 (d, 1H), 5.51 (t, 1H),6.19 (s, 1H), 6.35 (d, 1H), 6.83 (d, 1H), 6.91-6.96 (m, 1H), 7.04-7.11(m, 1H), 7.21 (d, 1H), 7.48 (t, 1H), 7.58 (d, 1H), 8.64 (d, 1H).

Example 1101-[(5-Chloro-1H-indazol-4-yl)amino]-6-fluoro-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol5-Chloro-4-nitro-1H-indazole

2.24 g (12 mmol) of 4-chloro-2-methyl-3-nitrophenylamine, producedaccording to the literature (Mori et al., Chem. Pharm. Bull. 1986, 34,4859 ff. as well as Brand and Zoller, Chem. Ber. 1907, 3324 ff.) isdissolved in 100 ml of acetic acid. At 10° C., 6.0 ml of a 2 molaraqueous sodium nitrite solution is added in drops. The suspension isthen added to boiling acetic acid (150 ml) within 15 minutes, and thereaction mixture is allowed to reflux for 4 hours. After the acetic acidis removed in a vacuum, the residue is taken up in ethyl acetate andsaturated sodium bicarbonate solution. The organic phase is washed withsaturated sodium chloride solution and dried on sodium sulfate. Afterthe solvent is removed in a vacuum, the crude product is further reacted(1.81 g, 76%).

¹H-NMR (300 MHz, DMSO-d₆): δ=7.65 (d, 1H), 7.97 (d, 1H), 8.32 (s, 1H),13.97 (s, 1H).

5-Chloro-1H-indazol-4-ylamine

A solution that consists of 5-chloro-4-nitro-1H-indazole (872 mg, 4.41mmol) is mixed with 150 mg of palladium on carbon (10%) and stirredunder hydrogen atmosphere at room temperature. After 45 minutes, thecatalyst is suctioned off on one frit and washed with methanol. Thefiltrate is concentrated by evaporation, and the residue is taken up in200 ml of ethyl acetate and heated. After renewed suctioning-off andconcentration by evaporation of the filtrate, the purification on silicagel is carried out with hexane/ethyl acetate (100-33% hexane). 296 mg(40% of theory) of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=5.97 (s, 2H), 6.66 (d, 1H), 7.05 (d, 1H),8.19 (s, 1H), 12.83 (s, 1H).

2-[(5-Chloro-1H-indazol-4-ylimino)-methyl]-1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-pentan-2-ol

A solution that consists of4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoro-methylpentanal(278 mg, 0.9 mmol) and 5-chloro-1H-indazol-4-ylamine (121 mg, 0.72 mmol)in 20 ml of xylene is mixed with titanium(IV)ethylate (0.42 ml, 2.0mmol) and refluxed for 10 hours. After cooling to room temperature,xylene is distilled off, and the residue is purified on silica gel withhexane/ethyl acetate (30-100% ethyl acetate). 123 mg (37% of theory) ofthe product is obtained.

¹H-NMR (400 MHz, CDCl₃): δ=1.43 (s, 3H), 1.57 (s, 3H), 2.38 (d, 1H),3.22 (d, 1H), 3.94 (d, 3H), 4.91 (s, 1H), 6.41-6.52 (m, 2H), 6.90 (d,1H), 7.28 (d, 1H), 7.38 (d, 1H), 7.56 (s, 1H), 7.72 (s, 1H), 10.26 (br,1H).

1-(5-Chloro-1H-indazol-4-ylamino)-6-fluoro-5-methoxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydro-naphthalen-2-ol

Analogously to Example 109, 27 mg (24% of theory) of the product isobtained in the reaction of2-[(5-chloro-1H-indazol-4-ylimino)-methyl]-1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-pentan-2-ol(111 mg, 0.24 mmol) with titanium tetrachloride (0.72 ml of a 1 Msolution in dichloromethane, 0.72 mmol) in 2.0 ml of dichloromethaneafter purification by means of preparative thin-layer chromatography.

¹H-NMR (400 MHz, CDCl₃): δ=1.56 (s, 3H), 1.65 (s, 3H), 2.09-2.17 (2d,2H), 3.97 (d, 3H), 5.34-5.36 (m, 2H), 6.87-6.95 (m, 2H), 7.15 (dd, 1H),7.32 (d, 1H), 8.05 (s, 1H).

Example 1111-(5-Methyl-1H-indazol-4-ylamino)-6-fluoro-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydro-naphthalene-2,5-diol5-Methyl-1H-indazol-4-ylamine

In a solution that consists of 2,4-dimethylaniline (12.4 ml, 100 mmol)in 80 ml of concentrated sulfuric acid, it is mixed at 0° C. with 5.0 mlof fuming nitric acid and stirred for 20 minutes at 4° C., and then for30 minutes at room temperature. The reaction mixture is poured into 600ml of ice water, and set at a pH of 10 with 5N sodium hydroxidesolution. The precipitate is suctioned off, washed with water and dried.15.72 g (95% of theory) of 2,4-dimethylnitrophenylamine is obtained as amixture of regioisomers.

Analogously to the production of 5-chloro-4-nitro-1H-indazole, 1.14 g(57% of theory) of the product was obtained as a mixture of the tworegioisomers in the reaction of 2,4-dimethylnitrophenylamine (2.0 g, 12mmol) with 6.0 ml of a 2 molar aqueous sodium nitrite solution in aceticacid (250 ml).

MS (ES+, acetonitrile/water 1:1+0.01% formic acid): m/z(%) 178 (M+1,100).

Analogously to the production of 5-chloro-1H-indazol-4-ylamine, theregioisomeric mixture of the previous reaction (1.0 g, 5.64 mmol)) isreacted with 100 mg of palladium on carbon in methanol under hydrogenatmosphere for 16 hours at room temperature. After purification onsilica gel with hexane/ethyl acetate (33% hexane, then 100% ethylacetate), 53 mg (6% of theory) of 5-methyl-1H-indazol-4-ylamine isobtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=2.12 (s, 3H), 5.41 (s, 2H), 6.57 (d, 1H),6.90 (d, 1H), 8.10 (s, 1H), 12.5 (s, 1H).

1-(5-Methyl-1H-indazol-4-ylamino)-6-fluoro-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalene-2,5-diol

4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal(308 mg, 1.0 mmol) and 5-methyl-1H-indazol-4-ylamine (148 mg, 1.0 mmol)are introduced into 15.0 ml of xylene and mixed withtitanium(IV)ethylate (0.42 ml, 2.0 mmol). After 3 hours under reflux,the reaction mixture is allowed to cool to room temperature. After ethylacetate and saturated sodium chloride solution are added, it is stirredvigorously for 30 minutes at room temperature. The deposited precipitateis suctioned off, the aqueous phase is separated, and the organic phaseis dried on sodium sulfate. The purification is carried out by means ofchromatography on silica gel with hexane/ethyl acetate (30-40% ethylacetate). 345 mg (79% of theory) of1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-[(5-methyl-1H-indazol-4-ylimino)methyl]-pentan-2-olis obtained.

1,1,1-Trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-[(5-methyl-1H-indazol-4-ylimino)-methyl]-pentan-2-ol(150 mg, 0.34 mmol) is mixed with boron tribromide (3.40 ml of a 1 Msolution in dichloromethane, 3.4 mmol) at room temperature. After 4hours at room temperature, the reaction mixture is allowed to standovernight at −30° C., then saturated sodium bicarbonate solution andethyl acetate are added. It is extracted with ethyl acetate, and thecombined organic phases are washed with saturated sodium chloridesolution and dried on sodium sulfate. After the solvent is removed in avacuum as well as purification by means of preparative thin-layerchromatography on silica gel with hexane/ethyl acetate (50% ethylacetate), 56 mg (39% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.61 (s, 3H), 1.68 (s, 3H), 2.09-2.14 (m,4H), 2.24 (d, 1H), 4.24-4.33 (br, 1H), 5.22-5.23 (m, 1H), 6.84-6.91 (m,3H), 7.14 (d, 1H), 8.04 (s, 1H).

MS (EI+): m/z(%)=423 (M+, 45), 147 (100).

Example 1127-Bromo-1-[(1H-indazol-4-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol(SL 4753-4)

¹H-NMR (300 MHz, CD₃OD): δ=1.52 (3H), 1.66 (3H), 2.00-2.22 (2H), 3.88(3H), 5.18 (1H), 6.35 (1H), 6.89 (1H), 7.05 (1H), 7.15-7.29 (2H), 8.13(1H).

Example 1135-[(2-Hydroxy-4,4-pentamethylene-2-(trifluoromethyl)-1,2,3,4-tetrahydro-1-naphthyl)amino]-2-quinolone5-[2-Hydroxy-4-phenyl-4,4-pentamethylene-2-trifluoromethylbutyl-1-imino]-2-quinolone

Analogously to Example 15, 150 mg of2-hydroxy-4-phenyl-4,4-pentamethylene-2-trifluoromethylbutyraldehyde iscondensed with 88 mg of 5-aminoquinolone in the presence of 0.21 ml oftitanium tetraethylate to form imine (102 mg).

¹H-NMR (300 MHz, CDCl₃): δ=1.40-2.05 (m, 10H), 2.40 (d, 1H), 2.65 (d,1H), 4.80 (br. s, 1H), 6.15 (d, 1H), 6.80 (d, 1H), 6.85 (t, 1H), 7.00(m, 2H), 7.20-7.35 (m, 4H), 8.20 (d, 1H), 12.00 (br. s, 1H).

5-[(2-Hydroxy-4,4-pentamethylene-2-(trifluoromethyl)-1,2,3,4-tetrahydro-1-naphthyl)amino]-2-quinolone

Analogously to Example 15, 100 mg of imine is converted with 4 ml of a 1M titanium tetrachloride-CH₂Cl₂ solution into 59 mg of product.

¹H-NMR (DMSO-d₆): δ=1.35-1.80 (m, 11H), 2.15 (m, 1H), 5.35 (d, 1H), 5.95(s, 1H), 6.25 (d, 1H), 6.40 (d, 1H), 6.55 (t, 2H), 7.15 (m, 2H), 7.25(t, 1H), 7.30 (m, 1H), 7.55 (d, 1H), 8.20 (d, 1H), 11.55 (br.s, 1H).

Example 114cis-1-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-diol

200 mg (3.1 mmol) of potassium cyanide in 2 ml of water is added to 0.55g (2.7 mmol) of 1,1,1-trifluoro-4-phenyl-butan-2-one (D. Yang; M-K.Wong; Z. Yan J. Org. Chem. (2000); 65; 4179-4184) in 4 ml of THF and 2ml of water. It is cooled to 0° C., and 1 ml of a 25% sulfuric acid isadded, allowed to heat to room temperature and stirred for 16 hours.Saturated sodium bicarbonate solution is added and extracted with ethylacetate. After washing with saturated sodium chloride solution anddrying on sodium sulfate, the crude cyanide, which is dissolved in 15 mlof diethyl ether and cooled to −70° C., is obtained quantitatively. 4.6ml (5.5 mmol) of a 1.2 M DIBAL solution in toluene is added in dropsover 10 minutes. It is allowed to heat for 2 hours to room temperature,quenched with 10% tartaric acid solution, and vigorous stirring iscontinued. After extraction with ethyl acetate, 5 g of silica gel and 10ml of a 1 M sulfuric acid are added. It is stirred vigorously for 12hours and filtered through Celite. The phases are separated, and it isextracted again with ethyl acetate. After chromatography on silica gel(hexane/ethyl acetate 30%), 300 mg of still contaminated2-hydroxy-4-phenyl-2-(trifluoromethyl)-butanal is obtained.

0.5 ml (2.4 mmol) of titanium tetraethylate is added to the thusobtained aldehyde and 200 mg (1.13 mmol) of5-amino-8-fluoro-2-methylquinazoline in 15 ml of toluene, and themixture is heated for 2 hours to 100° C. After the cooling, it is pouredinto water, and vigorous stirring is continued. The suspension isfiltered through Celite and thoroughly rewashed with ethyl acetate. Thephases of the filtrate are separated, and it is extracted again withethyl acetate. It is dried on sodium sulfate, and the solvent is removedin a vacuum. After chromatography on silica gel (hexane/ethyl acetate30%), 100 mg of1-(8-fluoro-2-methylquinazolin-5-ylimino)-4-phenyl-2-(trifluoromethyl)butan-2-olis obtained. The imine is taken up in 5 ml of dichloromethane and cooledto −70° C. 1 ml (1 mmol) of a 1 M titanium tetrachloride solution indichloromethane is added in drops over 10 minutes and stirred for onehour. The solution is poured into saturated sodium bicarbonate solutionand stirred vigorously for 15 minutes. It is extracted with ethylacetate, washed with saturated sodium chloride solution, and dried onsodium sulfate. After concentration by evaporation and chromatography onsilica gel (hexane/ethyl acetate 50%), 44 mg of the desired product isobtained.

¹H-NMR (300 MHz, CDCl₃): δ=2.25-2.32 (m, 2H), 2.91 (ddd, 1H), 2.92 (s,3H), 3.19 (ddd, 1H), 5.09 (d, 1H), 5.26 (d, 1H), 6.78 (dd, 1H),7.15-7.29 (m, 4H), 7.49 (dd, 1H), 9.34 (s, 1H).

Example 115cis-1-[(8-Fluoro-2-methylquinazolin-5-yl)amino-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CDCl₃): δ=1.59 (s, 3H), 1.72 (s, 3H), 2.11 (d, 1H),2.21 (d, 1H), 2.93 (s, 3H), 5.05 (d, 1H), 5.28 (br, 1H), 5.40 (d, 1H),6.66 (d, 1H), 6.71 (dd, 1H), 6.94 (d, 1H), 7.03 (t, 1H), 7.47 (dd, 1H),9.37 (s, 1H).

Example 116cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol5-Amino-7,8-difluoro-2-methyquinazoline

156 ml (391 mmol) of a 2.5 M butyllithium solution in hexane is added indrops to 41.7 g (180 mmol) of2,2-dimethyl-N-(3,4,5-trifluorphenyl)-propionamide in 385 ml of THF at−70° C. It is allowed to stir for one hour, and then 38.6 ml of DMF in90 ml of THF is added in drops, and the solution may heat to −60° C. Itis stirred for another hour at −70° C., and then the cold reactionsolution is poured into a mixture of 2 kg of ice and 400 ml ofconcentrated hydrochloric acid. It is stirred vigorously and extractedafter one hour several times with diethyl ether. The organic phase iswashed neutral with water and dried on sodium sulfate. Afterconcentration by evaporation, 49.3 g (188 mmol) of crude4,5,6-trifluoro-2-N-pivaloylaminobenzaldehyde is obtained, which isadded together with 26 g (275 mmol) of acetamidine hydrochloride, 38.3 g(277 mmol) of potassium carbonate and 30 g of molecular sieve (4A) in206 ml of butyronitrile. It is heated while being stirred vigorously for18 hours to 145° C., and the solvent is removed in a vacuum. After theresidue is chromatographed on silica gel with hexane/ethyl acetate(0-100%), 9.1 g of 7,8-difluoro-5-N-pivaloylamino-2-methylquinazoline isobtained.

2.0 g (7.2 mmol) of 7,8-difluoro-5-N-pivaloylamino-2-methyquinazoline isdissolved in 140 ml of toluene and cooled to −70° C. 24 ml (28.8 mmol)of a 1.2 M diisobutyl aluminum hydride solution in toluene is added indrops over 30 minutes. The reaction mixture is allowed to heat to −25°C. over 2 hours and stirred for 2 hours at −25° C. Isopropanol and thenwater are slowly added and stirred for 12 hours at room temperatureuntil a precipitate, which is removed by means of filtration throughCelite, is formed. It is rewashed well with a methylenechloride/methanol mixture and concentrated by evaporation. The residueis vigorously stirred in 200 ml of ethyl acetate and 50 ml of methanoltogether with 100 g of silica gel and 20 g of manganese dioxide. It isfiltered through Celite, rewashed well with a methylenechloride-methanol mixture and concentrated by evaporation. Afterchromatography on silica gel with hexane-ethyl acetate (0-100%), 370 mgof the product is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=2.81 (s, 3H), 6.64 (dd, 1H), 9.52 (s, 1H).

cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.46 (s, 3H), 1.61 (s, 3H), 2.20 (d, 1H),2.24 (d, 1H), 2.91 (s, 3H), 5.00 (d, 1H), 5.86 (d, 1H), 6.56 (dd, 1H),6.71 (dd, 1H), 7.18 (t, 1H), 7.29 (d, 1H), 7.32 (t, 1H), 7.43 (d, 1H),9.28 (s, 1H).

Example 117cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-6-fluoro-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.59 (s, 3H), 1.70 (s, 3H), 2.12 (d, 1H),2.22 (d, 1H), 2.91 (s, 3H), 3.98 (s, 3H), 4.90 (d, 1H), 5.80 (d, 1H),6.56 (dd, 1H), 6.94 (dd, 1H), 7.00 (dd, 1H), 9.24 (s, 1H).

Example 1185-{[2-Hydroxy-4,4-dimethyl-2,5-bis(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino}-quinolin-2(1H)-one

The production is performed as described in Example 15 (13). Thecyclization of the imine to the product is carried out intrifluoroacetic acid under reflux, however, instead of with TiCl₄ intoluene.

¹H-NMR (300 MHz, CDCl₃): δ=1.55 (s, 3H), 1.65 (s, 3H), 2.05 (d, 1H),2.30 (d, 1H), 5.10 (d, 1H), 5.30 (d, 1H), 6.35 (d, 1H), 6.60 (d, 1H),6.70 (d, 1H) 7.25 (m, 1H), 7.30 (t, 1H), 7.55 (d, 1H), 7.75 (d, 1H),7.95 (d, 1H), 10.85 (br.s, 1H).

MS (ES): MH⁺: 471.

Example 1195-{[6-Chloro-2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino-quinolin-2(1H)-one

The synthesis is carried out as described in Example 15.

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (s, 3H), 1.60 (s, 3H), 2.10 (d, 1H),2.20 (d, 1H), 5.05 (br., 1H), 5.70 (br., 1H), 6.50 (d, 1H), 6.60 (m,2H), 7.05 (dd, 1H), 7.20 (d, 1H), 7.35 (m, 2H), 8.30 (d, 1H), 10.40(br., 1H).

MS (ES): MH+: 437/439 (3:1).

Example 1205-{[2-Hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-1-methylquinolin-2(1H)-one

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (s, 3H), 1.60 (s, 3H), 2.10 (d, 1H),2.20 (d, 1H), 3.60 (s, 3H), 5.15 (d, 1H), 5.45 (d, 1H), 6.60 (d, 1H),6.65 (d, 1H), 6.75 (d, 1H), 7.10 (t, 1H), 7.30 (m, 1H), 7.40 (m, 2H),8.00 (d, 1H).

MS (ES): MH⁺: 417.

Example 1215-{[2-Hydroxy-4,4-dimethyl-2-(trifluoromethyl)-5,6-trimethylene-1,2,3,4-tetrahydronaphthalen-1-yl]amino1-quinolin-2(1H)-one

¹H-NMR (300 MHz, CDCl₃): δ=1.45 (s, 3H), 1.65 (s, 3H), 1.95-2.15 (m,3H), 2.20 (d, 1H), 2.80 (m, 2H), 3.15 (m, 2H), 5.10 (d, 1H), 5.25 (d,1H), 6.55 (m, 3H), 7.00 (d, 11H), 7.10 (d, 1H), 7.30 (t, 11H), 8.00 (d,1H), 10.10 (br., 1H).

MS (ES): MH⁺: 443.

Enantiomer separation is carried out by chiral HPLC (Chiralpak AD 20μcolumn with hexane-ethanol 95:5 as an eluant); the (−)-enantiomer iseluted at 11.4 minutes, the (+)-enantiomer at 14.1 minutes.

Example 1225-{[6-Chloro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

¹H-NMR (300 MHz, CDCl₃): δ=1.55 (s, 3H), 1.70 (s, 3H), 2.10 (d, 1H),2.20 (d, 1H), 3.95 (s, 3H), 5.05 (d, 1H), 5.35 (d, 1H), 6.55 (m, 3H),7.00 (d, 1H), 7.15 (d, 1H), 7.35 (t, 1H), 8.05 (d, 1H), 9.95 (br., 1H).

MS (ES): MH⁺: 467/469 (3/1).

Example 1235-{[6-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

¹H-NMR (300 MHz, CDCl₃): δ=1.60 (s, 3H), 1.70 (s, 3H), 2.05 (d, 1H),2.20 (d, 1H), 4.20 (br., 1H), 5.05 (d, 1H), 5.40 (d, 1H), 5.95 (br.s,1H), 6.55 (m, 3H), 6.85 (d, 1H), 7.10 (d, 1H), 7.35 (t, 1H), 8.10 (d,1H), 9.75 (br., 1H).

MS (ES): MH⁺: 453/455 (3/1).

Enantiomer separation is carried out by chiral HPLC (Chiracel OD 20μcolumn with hexane-ethanol 85:15 as an eluant); the (+)-enantiomer iseluted at 10.4 minutes, the (−)-enantiomer at 14.8 minutes.

(+)-Enantiomer:

¹H-NMR ([D]₆-DMSO): δ=1.50 (s, 3H), 1.65 (s, 3H), 1.95 (d, 1H), 2.10 (d,1H), 5.30 (d, 1H), 6.05 (s, 1H), 6.20 (d, 1H), 6.40 (d, 1H), 6.55 (m,2H), 6.70 (d, 1H), 7.20 (m, 2H), 8.20 (d, 1H), 9.05 (s, 1H), 11.55 (s,1H).

(−)-Enantiomer:

¹H-NMR ([D]₆-DMSO): δ=1.50 (s, 3H), 1.65 (s, 3H), 1.95 (d, 1H), 2.10 (d,1H), 5.30 (d, 1H), 6.05 (s, 1H), 6.20 (d, 1H), 6.40 (d, 1H), 6.55 (m,2H), 6.70 (d, 1H), 7.20 (m, 2H), 8.20 (d, 1H), 9.05 (s, 1H), 11.55 (s,1H).

Example 1245-{[5-Bromo-2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

The cyclization of the imine precursor to the product is carried out intrifluoroacetic acid under reflux instead of with TiCl₄ in toluene.

¹H-NMR (300 MHz, CDCl₃): δ=1.70 (s, 3H), 1.85 (s, 3H), 2.10 (d, 1H),2.25 (d, 1H), 5.10 (d, 1H), 5.40 (d, 1H), 6.50 (d, 1H), 6.55 (d, 1H),6.60 (d, 1H), 6.90 (t, 1H), 7.30 (d, 1H), 7.35 (t, 1H), 7.55 (d, 1H),8.05 (d, 1H), 10.40 (br. s, 1H).

MS (ES): MH⁺: 481/483 (1/1).

Example 1255-{[6-Chloro-2-hydroxy-5-methoxy-2-(trifluoromethyl)-4,4-trimethylene-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

¹H-NMR (300 MHz, CDCl₃): δ=2.05-2.40 (m, 5H), 2.60 (d, 1H), 2.85 (m,2H), 4.10 (s, 3H), 4.95 (d, 1H), 5.05 (d, 1H), 6.55 (m, 2H), 6.65 (d,1H), 6.70 (d, 1H), 6.95 (d, 1H), 7.15 (d, 1H), 7.35 (t, 1H), 7.90 (d,1H), 10.50 (br., 1H).

MS (ES): MH⁺: 478/480 (3/1).

Example 1265-{[6-Chloro-2,5-dihydroxy-2-(trifluoromethyl)-4,4-trimethylene-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

¹H-NMR ([D]₆-DMSO): δ=1.80 (m, 1H), 2.05 (m, 2H), 2.20 (d, 1H), 2.30 (m,1H), 2.60 (d, 1H), 2.90 (q, 1H), 3.25 (q, 1H), 5.30 (d, 1H), 5.90 (s,1H), 6.10 (d, 1H), 6.35 (d, 1H), 6.55 (d, 2H), 6.70 (d, 1H), 7.20 (d,1H), 7.25 (t, 1H), 8.15 (d, 1H), 9.30 (s, 1H), 11.55 (br.S, 1H).

MS (ES): MH⁺: 465/467 (3/1).

Enantiomer separation is carried out by chiral HPLC (Chiralpak AD 20μcolumn with hexane-ethanol as an eluant); the (−)-enantiomer is firsteluted.

¹H-NMR ([D]₆-DMSO): δ=1.80 (m, 1H), 2.05 (m, 2H), 2.20 (d, 1H), 2.30 (m,1H), 2.60 (d, 1H), 2.90 (q, 1H), 3.25 (q, 1H), 5.30 (d, 1H), 5.90 (s,1H), 6.10 (d, 1H), 6.35 (d, 1H), 6.55 (d, 2H), 6.70 (d, 1H), 7.20 (d,1H), 7.25 (t, 1H), 8.15 (d, 1H), 9.30 (s, 1H), 11.55 (br. S, 1H).

(+)-Enantiomer:

¹H-NMR ([D]₆-DMSO): δ=1.80 (m, 1H), 2.05 (m, 2H), 2.20 (d, 1H), 2.30 (m,1H), 2.60 (d, 1H), 2.90 (q, 1H), 3.25 (q, 1H), 5.30 (d, 1H), 5.90 (s,1H), 6.10 (d, 1H), 6.35 (d, 1H), 6.55 (d, 2H), 6.70 (d, 1H), 7.20 (d,1H), 7.25 (t, 1H), 8.15 (d, 1H), 9.30 (s, 1H), 11.55 (br. S, 1H).

Example 1275-{[5-Difluoromethoxy-2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

The cyclization of the imine to the product is carried out intrifluoroacetic acid under reflux instead of with TiCl₄ in toluene.

¹H-NMR ([D]₆-DMSO): δ=1.45 (s, 1H), 1.60 (s, 1H), 2.00 (d, 1H), 2.15 (d,1H), 5.40 (d, 1H), 6.15 (s, 1H), 6.20 (d, 1H), 6.40 (d, 1H), 6.55 (d,1H),6.60 (d, 1H), 7.05 (m, 2H), 7.20 (t, 1H), 7.30 (t, CHF₂, J_(HF)=75Hz), 8.20 (d, 1H), 11.55 (s, 1H).

MS (ES): MH⁺: 469.

Example 1284-{[6-Chloro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-indazole

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (s, 3H), 1.55 (s, 3H), 2.05 (d, 1H),2.20 (d, 1H), 5.15 (br., 2H), 6.40 (d, 1H), 6.90 (d, 1H), 7.05 (dd, 1H),7.25-7.35 (m, 4H), 8.55 (br., 1H).

MS (ES): MH⁺=410/412 (3:1);

Example 129 5-(6-Chloro-2-hydroxy-7-methoxy-4,4dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one4-(3-Chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-[(trifluoromethyl)-pentanal

75 ml of methylmagnesium chloride (22% in THF) is introduced into 200 mlof THF and at 0° C., a solution of 9.17 g (45.7 mmol) ofmethyl-3-chloro-4-methoxybenzoate in 200 ml of THF is added in dropswithin 1 hour. After the conversion is completed, the reaction is endedby the addition of 30 ml of saturated ammonium chloride solution, andthe mixture is dispersed between ethyl acetate and water. The aqueousphase is extracted with ethyl acetate, the combined organic phases arewashed with water and saturated sodium chloride solution, dried withsodium sulfate, and concentrated by evaporation in a rotary evaporator.

4.5 g (22.4 mmol) of the crude product (yield 98%) is introduced into100 ml of dichloromethane and first 6.0 g (42.7 mmol) of2-trimethylsilanyloxy-acrylic acid ethyl ester, and then 1.85 ml of tintetrachloride are added in drops at −70° C. After 10 minutes, thereaction mixture is added to saturated potassium carbonate solution. Theaqueous phase is extracted with dichloromethane, the combined organicphases are washed with 1 M hydrochloric acid solution, water andsaturated sodium chloride solution, dried with sodium sulfate andconcentrated by evaporation in a rotary evaporator. After columnchromatography (silica gel, hexane/ethyl acetate 9:1), 2.0 g (29%) ofthe desired intermediate products is obtained.

1.5 g (5.0 mmol) of this ketoester is mixed in THF at −70° C. with 2.1ml of trimethyl-trifluoromethylsilane and 620 μl of tetrabutylammoniumfluoride (1 M solution in THF). It is allowed to thaw to roomtemperature and to stir for 18 hours, then the mixture is mixed at 0° C.with 6 ml of tetrabutylammonium fluoride (1 M solution in THF). Afteranother 10 minutes, the mixture is dispersed between ethyl acetate and 1M hydrochloric acid solution. The aqueous phase is extracted with ethylacetate, the combined organic phases are washed with 1 M hydrochloricacid solution, water and saturated sodium chloride solution, dried withsodium sulfate, and concentrated by evaporation in a rotary evaporator.1.81 g of the desired intermediate product, which, dissolved in 15 ml ofdiethyl ether, is added in drops at 0° C. to a suspension of 0.40 g oflithium aluminum hydride in diethyl ether, is obtained. After 1 hour at0° C. and 18 hours at room temperature, the reaction is completed byadding 25 ml of saturated sodium bicarbonate solution. The precipitatethat is formed is filtered off, rewashed with ethyl acetate, and thefiltrate is washed with saturated sodium chloride solution, dried withsodium sulfate and concentrated by evaporation in a rotary evaporator.After column chromatography (silica gel, hexane/ethyl acetate 8:2), 1.04g (65%) of the desired diol intermediate product is obtained.

109 μl (1.12 mmol) of oxalyl chloride is introduced intodichloromethane, and first 190 μl (2.68 mmol) of DMSO and, after 15minutes of stirring, a solution of 366 mg (1.12 mmol) of the diolintermediate stage in dichloromethane are added in drops at

−75° C. After another 15 minutes, 830 μl (5.62 mmol) of triethylamine isadded in drops (at −50°). It is allowed to slowly thaw and stirred foranother 18 hours. The reaction is completed by adding saturated ammoniumchloride solution, the phases are separated, and the aqueous phase isextracted with dichloromethane. The combined organic phases are washedwith 1 M hydrochloric acid solution, water and saturated NaCl solutionand dried with NaSO₄. It is concentrated by evaporation andchromatographed on silica gel with hexane/ethyl acetate (4:1). 302 mg(84%) of the desired4-(3-chloro-4-methoxy-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanalis obtained.

¹H-NMR (CDCl₃): δ=1.34 (s, 3H), 1.40 (s, 3H), 2.30 (d, 1H), 2.62 (d,1H), 3.66 (s, 1H), 3.90 (s, 3H), 6.84 (d, 1H), 7.13 (dd, 1H), 7.31 (d,1H), 8.90 (s, 1H).

5-(6-Chloro-2-hydroxy-7-methoxy-4,4dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one

100 mg (0.31 mmol) of4-(3-chloro-4-methoxy-phenyl-2-hydroxy-4-methyl-2-trifluoromethyl-pentanaland 50 mg (0.31 mmol) of 5-amino-1H-quinolin-2-one are introduced into30 ml of toluene and 0.16 ml of titanium tetraethylate is added indrops. The mixture is stirred for 1 hour at a bath temperature of 100°C. After cooling, the solution is added to ice, several ml of saturatedsodium bicarbonate solution is added, it is filtered off on diatomaceousearth and rewashed with ethyl acetate and water. The phases areseparated, the aqueous phase is extracted with ethyl acetate, thecombined organic phases are washed with water and saturated sodiumchloride solution, dried with sodium sulfate and concentrated byevaporation in a rotary evaporator. The imine (30%) that is obtainedafter chromatographic purification (silica gel, hexane/ethyl acetate95:5 to 25:75) is taken up again in dichloromethane and mixed at −50° C.with 3.6 ml of titanium tetrachloride (1 M in toluene). It is allowed tothaw, and the mixture is added to ice after 18 hours of stirring, thephases are separated, extracted with dichloromethane, washed withsaturated sodium chloride solution and dried with sodium sulfate. Afterconcentration by evaporation in a rotary evaporator, the crude productis chromatographed on silica gel (eluant: 2% methanol indichloromethane). The product that is obtained is recrystallized fromhexane/diethyl ether (yield: 28%).

Melting point: 182° C.;

¹H-NMR (CD₃OD): δ=1.28 (s, 3H), 1.42 (s, 3H), 1.95 (d, 1H), 2.07 (d,1H), 3.54 (s, 3H), 4.88 (s, 1H), 6.42-6.48 (m, 2H), 6.58 (d, 1H), 6.82(s, 1H), 7.25-7.30 (m, 2H), 7.97 (d, 1H).

Example 1305-(6-Chloro-2-hydroxy-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one

This compound was produced with use of the aldehyde that is described inExample 129 above and the corresponding amine.

Melting point: 85° C., MS (ESI): 47 (M+1).

Example 1315-(6-Chloro-2-hydroxy-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-12,4-tetrahydronaphthalen-1-ylamino)-2H-phthalazin-1-one

Example 131 was produced as described in Example 129 with use of thecorresponding starting materials.

¹H-NMR (CD₃OD): δ=1.39 (s, 3H), 1.53 (s, 3H), 2.16 (dd, 2H), 3.12 (s,3H), 5.30 (s, 1H), 6.94 (s, 1H), 7.31 (dd, 1H), 7.42 (s, 1H), 7.64-7.71(m, 2H), 8.59 (s, 1H).

Example 1326-Chloro-7-methoxy-4,4-dimethyl-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

Example 132 was synthesized with use of the corresponding startingmaterials as described in Example 129.

¹H-NMR (CDCl₃): δ=1.39 (s, 3H), 1.52 (s, 3H), 2.15 (dd, 2H), 2.73 (s,3H), 3.49 (s, 3H), 4.97 (d, 1H), 5.10 (d, 1H), 6.80-6.84 (m, 2H), 7.24(d, 1H), 7.36 (s, 1H), 7.49 (d, 1H), 7.55 (dd, 1H), 8.08 (d, 1H).

Example 1336-Chloro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-7-methoxy-4,4-dimethyl-2-(trifluoromethyl-1,2,3,4-tetrahydronaphthalen-2-ol

The compound was produced analogously to Example 129.

¹H-NMR (CDCl₃): δ=1.42 (s, 3H), 1.56 (s, 3H), 2.19 (dd, 2H), 3.62 (s,3H), 4.31 (s, br, 1H), 5.01 (d, 1H), 5.56 (d, 1H), 6.70 (dd, 1H), 6.90(s, 1H), 7.39 (s, 1H), 7.46-7.52 (m, 1H), 9.39 (s, 1H).

Example 1345-(6-Chloro-2,7-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one

20 mg of5-[4-(3-chloro-4-methoxyphenyl)-2,2-dihydroxy-4-methylpentylamino]-1H-quinolin-2-one(43 μmol) is introduced into dichloromethane, mixed with 0.86 mmol ofboron tribromide (1 M solution in dichloromethane), and stirred for 3hours at room temperature. The reaction is completed with saturatedsodium bicarbonate solution. It is extracted with dichloromethane, theorganic phases are washed with saturated sodium chloride solution anddried with sodium sulfate and concentrated by evaporation. The crudeproduct is recrystallized from hexane/diethyl ether. 9 mg (40%) of thedesired product is obtained.

Melting point: 158° C.; MS (ESI): 453 (M+1).

Example 1351-(8-Fluoro-2-methylquinazolin-5-ylamino)-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol2-Hydroxy-4-(4-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal

The aldehyde was produced from 4-methoxybenzyl cyanide as described inExample 5.

¹H-NMR (CDCl₃): δ=1.34 (s, 3H), 1.43 (s, 3H), 2.30 (d, 1H), 2.69 (d,1H), 3.66 (s, 1H), 3.80 (s, 3H), 6.85 (d, 2H), 7.21 (d, 2H), 8.76 (s,1H).

1-(8-Fluoro-2-methylquinazolin-5-ylamino)-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The above compound was produced with use of the corresponding startingmaterials, as described in Example 129.

Melting point 97° C.; MS (ESI): 450 (M+1).

Example 1365-(2-Hydroxy-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one

The production was carried out as described in Example 129 with use ofthe 2-hydroxy-4-(4-methoxyphenyl-4-methyl-2-(trifluoromethyl)-pentanaland the corresponding amine.

Melting point 128° C.; MS (ESI): 433 (M+1).

Example 1375-(2-Hydroxy-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one

The production was carried out as described in Example 129 with use ofthe 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanaland the corresponding amine.

Melting point 112° C.; MS (ESI): 433 (M+1).

Example 1385-(2-Hydroxy-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-phthalazin-1-one

The production was carried out as described in Example 129 with use ofthe 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanaland the corresponding amine.

Melting point 197° C.; MS (ESI): 434 (M+1).

Example 1397-Methoxy-4,4-dimethyl-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The production was carried out as described in Example 129 with use of2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal andthe corresponding amine.

Melting point 84° C.; MS (ESI): 431 (M+1).

The racemate was separated into the enantiomers with the aid of chiralHPLC.

Analytic HPLC: Chiralpak AD 10μ, 250×4.6 mm, 1 ml min¹, hexane/ethanol90/10

(+)-Enantiomer: R_(t)=7.0 minutes; melting point 84° C.; MS (ESI); 431(M+1);

-   -   (−)-Enantiomer: R_(t)=17.8 minutes; melting point 85° C.; MS        (ESI): 431 (M+1); specific optical rotation: −5.9 (c=0.14,        CHCl₃).

Example 1404,4-Dimethyl-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,7-diol

The ether that is described in Example 139 was subjected to ethercleavage with BBr₃ analogously to Example 134.

Melting point 127° C.; MS (ESI): 417 (M+1).

Example 1415-(2,7-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-phthalazin-1-one

The ether that is described in Example 138 was subjected to ethercleavage with BBr₃ analogously to Example 134.

Melting point 116° C.; MS (ESI): 420 (M+1).

Example 1421-(8-Fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalene-2.7-diol.

The ether that is described in Example 135 was subjected to ethercleavage with BBr₃ analogously to Example 134.

¹H-NMR (CD₃OD): δ=1.41 (s, 3H), 1.54 (s, 3H), 2.02 (d, 1H), 2.17 (d,1H), 2.82 (d, 3H), 4.32 (s, 1H), 6.93 (dd, 1H), 7.01 (d, 1H), 7.32-7.43(m, 2H), 7.52-7.66 (m, 3H); MS (ESI): 436 (M+1).

Example 1435-(2,7-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one

The ether that is described in Example 136 was subjected to ethercleavage with BBr₃ analogously to Example 134.

¹H-NMR (CD₃OD): δ=1.38 (s, 3H), 1.52 (s, 3H), 2.13 (dd, 2H), 5.17 (s,1H), 6.53 (d, 1H), 6.62 (d, 1H), 6.68-6.78 (m, 2H), 7.26 (d, 1H), 7.39(dd, 1H), 8.26 (d, 1H);

MS (ESI): 419 (M+1).

Example 1445-(2-Hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one

The compound above was produced as described in Example 129 with use of2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal andthe corresponding amine.

Melting point 228° C.; MS (ESI): 405 (M+1)

Example 1451-(8-Fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol

The compound above was produced as described in Example 129 with use of2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal andthe corresponding amine.

Melting point 132° C.; MS (ESI): 422 (M+1)

Example 1467-Chloro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol2-Chloro-5-methylanisole

50 g (350.65 mmol) of 2-chloro-5-methylphenol is dissolved in 450 ml ofacetone and mixed with 96.5 g (701.3 mmol) of potassium carbonate undernitrogen. After 43.6 ml of methyl iodide (2 equivalents) is added, it isrefluxed for three hours. After cooling, the reaction mixture isfiltered, the filter residue is washed with acetone, and the filter isspun in until a dry state is reached (bath temperature 30° C.). Sincethe residue still contains potassium carbonate, it is taken up in alittle diethyl ether and filtered again. After the solvent is spun off,57 g (103.8%) of the desired compound is obtained, which is used ascrude product in the next stage.

¹H-NMR (300 MHz, CDCl₃): δ=2.35 (3H), 3.90 (3H), 6.68-6.79 (2H), 7.22(1H).

4-Chloro-3-methoxybenzylbromide

57 g (363.96 mmol) of 2-chloro-5-methylanisole is dissolved in 800 ml ofcarbon tetrachloride and mixed at room temperature with 69.9 g (393.08mmol) of N-bromosuccinimide. After 174.6 mg of benzoyl peroxide isadded, it is refluxed for five hours (bath temperature 105° C.). Thereaction mixture is suctioned off through a glass-pleated filter,rewashed, and the solution is spun in in a rotary evaporator. 83.6 g(97.5%) of the desired product (COntains traces of starting material anddibromide) is obtained, which is incorporated in crude form into thenext stage.

¹H-NMR (300 MHz, CDCl₃): δ=3.91 (3H), 4.48 (2H), 6.90-6.98 (2H), 7.32(1H).

4-Chloro-3-methoxybenzylcyanide

83.6 g (354.97 mmol) of the crude bromide is dissolved in 255 ml of DMFand mixed with 266 ml of water. After 34.7 g (532.45 mmol) of potassiumcyanide is added (heating), the mixture is stirred for three hours atroom temperature. The reaction mixture is poured into one liter of icewater and extracted three times with 500 ml each of diethyl ether. Thecombined organic extracts are washed with water and brine. After dryingon sodium sulfate, it is filtered, and the solvent is spun off. Theresidue is chromatographed on silica gel (mobile solvent ethylacetate/hexane). 44.7 g (69.4%) of the desired compound is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=3.75 (2H), 3.94 (3H), 6.80-6.91 (2H), 7.38(1H).

2-(4-Chloro-3-methoxyphenyl)-2-methylpropanenitrile

44.7 g (246.1 mmol) of the above-described nitrile is dissolved in 380ml of DMF and mixed with 69.8 g (492.2 mmol) of methyl iodide. Aftercooling to 0° C., 21.5 g (492.2 mmol) of NaH (55% suspension) is addedin portions to the reaction mixture within three and V₂ hours. After 18hours at room temperature, the batch is poured into 600 ml of ice waterand extracted three times with 500 ml each of diethyl ether. Thecombined organic phases are washed with water and brine. After drying onsodium sulfate, the desiccant is filtered of, and the solvent is spunoff in a rotary evaporator. After chromatography on silica gel (mobilesolvent ethyl acetate/hexane), 42.37 g (81.1%) of the desired compoundis obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.75 (6H), 3.96 (3H), 6.97 (1H), 7.07 (1H),7.49 (1H).

2-(4-Chloro-3-methoxyphenyl)-2-methylpropanal

25 g (119.23 mmol) of the above-described nitrile is dissolved in 475 mlof toluene. At −65° C. to −60° C., 149 ml of a 1.2 molar solution ofDIBAH in toluene is added in drops within 60 minutes. After two hours ofstirring at this temperature, the dropwise addition of 681 ml of a 20%L-(+)-tartaric acid solution is begun. After 200 milliliters, thetemperature is increased to −10° C. The remainder of the tartaric acidsolution is quickly added, and the batch is vigorously stirred for 16hours at room temperature. The reaction mixture is shaken twice with 600ml each of diethyl ether. The combined organic extracts are shaken withwater and brine, dried, and the solvent is spun off. The residue that isobtained (25 g=98.8%) is incorporated in crude form into the next stage.

¹H-NMR (300 MHz, CDCl₃): δ=1.48 (6H), 3.90 (3H), 6.70-6.88 (2H), 7.37(1H), 9.49 (1H).

Ethyl-E-4-(4-chloro-3-methoxyphenyl)-4-methylpent-2-enoate

25.6 g (114.3 mmol) of triethylphosphonacetate is introduced into 148 mlof tetrahydrofuran. At 0° C., 60.8 ml of a 2 M solution of LDA inTHF/heptane/ethylbenzene is added in drops (one and one-fourth hours).After one hour of stirring, 22.1 g (103.91 mmol) of2-(4-chloro-3-methoxyphenyl)-2-methylpropanal, dissolved in 100 ml oftetrahydrofuran, is added in drops at 0° C. After five days of stirringat room temperature, the reaction mixture is poured into 200 ml ofdilute ammonium chloride solution and extracted twice with 300 ml eachof diethyl ether. The combined organic extracts are treated as usual,and the residue that is obtained is chromatographed on silica gel(mobile solvent ethyl acetate/hexane). 24.1 g (82%) of the desiredcompound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.30 (3H), 1.47 (6H), 3.90 (3H), 4.20 (2H),5.80 (1H), 6.80-6.88 (2H), 7.09 (1H), 7.29 (1H).

Ethyl-4-(4-chloro-3-methoxyphenyl)-4-methylpentanoate

24.1 g (85.23 mmol) ofethyl-E-4-(4-chloro-3-methoxyphenyl)-4-methylpent-2-enoate is mixed in228 ml of ethyl acetate with 2.41 g of palladium on carbon (10%), and itis stirred overnight at room temperature under hydrogen atmosphere. Thecatalyst is removed by filtration through a glass-fiber filter, and theresidue that remains after concentration by evaporation (24.1 g=99.1%)is incorporated in crude form into the next stage.

¹H-NMR (300 MHz, CDCl₃): δ=1.21 (3H), 1.34 (6H), 1.90-2.10 (4H), 3.92(3H), 4.10 (2H), 6.82-6.90 (2H), 7.29 (1H).

Ethyl-4-(4-chloro-3-methoxyphenyl)-2-hydroxy-4-methylpentanoate

24.1 g (84.63 mmol) ofethyl-4-(4-chloro-3-methoxyphenyl)-4-methylpentanoate is dissolved in296 ml of tetrahydrofuran, and the reaction mixture is cooled to −70° C.to −65° C. Within 1¾ hours, 236.9 ml of a 0.5 molar solution ofpotassium-bis-(trimethylsilylamide) in toluene is added in drops, andthe reaction mixture then is stirred for 75 more minutes at −70° C. 30.9g (118.48 mmol) of Davis reagent, dissolved in 296 ml oftetrahydrofuran, is now added in drops within 60 minutes. After twohours of stirring at −70° C., 152 ml of saturated ammonium chloridesolution is slowly added in drops, the cold bath is removed, and it isvigorously stirred for 30 minutes. After extraction with diethyl ether,the combined organic extract are treated as usual with water and brine.After the solvent is spun off, the residue is chromatographed on silicagel (mobile solvent ethyl acetate/hexane). 21.4 g (84.2%) of the desiredcompound is isolated (easily contaminated).

Ethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-oxopentanoate

6.15 g (20.45 mmol) of ethyl4-(4-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-pentanoate is dissolvedin 213 ml of dichloromethane and mixed with 71 ml of dimethyl sulfoxide.After 10.3 g (102.23 mmol) of triethylamine is added, the batch is mixedin portions with 8.1 g (51.12 mmol) of SO₃/pyridine complex and thenstirred overnight at room temperature. The reaction mixture is mixedwhile being cooled slightly with 81 ml of saturated ammonium chloridesolution and vigorously stirred. After 2× extraction with diethyl ether,the combined organic phases are treated as usual. The residue thatremains after the solvent is spun off is chromatographed on silica gel(mobile solvent ethyl acetate/hexane) together with the residue thatresults from another batch (15.27 g). 15.46 g (72.9%, from the twobatches) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.25 (3H), 1.48 (6H), 3.16 (2H), 3.90 (3H),4.12 (2H), 6.83-6.94 (2H), 7.28 (1H).

(rac.)Ethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl-2-(trimethylsilyloxy)-pentanoate

15.46 g (51.75 mmol) ofethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-oxopentanoate is dissolvedin 85 ml of tetrahydrofuran and mixed at 0° C. with 8.83 g (62.09 mmol)of (trifluoromethyl)-trimethylsilane. After 126.8 mg oftetrabutylammonium fluoride is added, it SEQ ID No: stirred for twohours at 0 to 5° C. The batch is added to 150 ml of ice water, extractedtwice with diethyl ether, and the combined organic extracts are treatedas usual. After the solvent is spun off, the residue is chromatographedon silica gel (mobile solvent ethyl acetate/hexane). 14.11 g (61.8%) ofthe desired product (COntaminated), which is incorporated into the nextstage, is isolated.

MS (CI): 458 (100%).

Ethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl-2-hydroxy-pentanoate

8.9 g (20.18 mmol) of contaminatedethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl-2-(trimethylsilyloxy)-pentanoateis dissolved in 116 ml of tetrahydrofuran and mixed at room temperaturewith 6.37 g (20.18 mmol) of tetrabutylammonium fluoride trihydrate andstirred for one hour at room temperature. The reaction mixture is mixedwith water and extracted twice with 250 ml each of diethyl ether. Thecombined organic extracts are washed with water and with brine. Afterdrying on sodium sulfate, the desiccant is filtered off, the solvent isspun off, and the remaining residue is chromatographed on silica gel(mobile solvent ethyl acetate/hexane). 4.03 g (54.2%) of the desiredcompound is isolated. Other preparations are performed analogously.

¹H-NMR (300 MHz, CDCl₃): δ=1.19 (3H), 1.39 (3H), 1.49 (3H), 2.28 (1H),2.49 (1H), 3.60-3.71 (2H), 3.93 (3H), 3.98-4.10 (1H), 6.82-6.93 (2H),7.28 (1H).

4-(4-Chloro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal

5.25 g (14.24 mmol) of (rac.)ethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoateis dissolved in 53 ml of diethyl ether and mixed at 0° C. with 405.2 mg(10.68 mmol) of lithium aluminum hydride within 30 minutes. The reactionmixture is stirred for 1¼ more hours at 0° C. For hydrolysis, themixture is mixed drop by drop with 12.5 ml of saturated sodiumbicarbonate solution while being cooled in an ice bath. It is stirredvigorously for 30 minutes while being cooled in an ice bath and for 60minutes at room temperature. The precipitate is suctioned off and washedwith diethyl ether. The filtrate is concentrated by evaporation in arotary evaporator, and the residue is chromatographed on silica gel(mobile solvent ethyl acetate/hexane). 3.29 g (71.2%) of the desiredaldehyde, which still contains some starting ester and 54.7 mg of thecorresponding diol, is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.39 (3H), 1.48 (3H), 2.34 (1H), 2.69 (1H),3.69 (1H), 3.92 (3H), 6.80-6.93 (2H), 7.30 (1H), 8.90 (1H).

4-(4-Chloro-3-methoxy-phenyl)-1,1,1-trifluoro-2-{[(E)-8-fluoro-2-methyl-quinazolin-5-ylimino]-methyl}-4-methyl-pentan-2-ol

350 mg (1.08 mmol) of(rac.)-4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanalis mixed in 5.8 ml of o-xylene with 190.9 mg (1.08 mmol) of5-amino-8-fluoro-2-methylquinazoline. After 0.64 ml (2.16) titanium(IV)isopropylate is added, it is refluxed for three hours (bath temperature120° C.). After cooling, the batch is added to saturated sodium chloridesolution and stirred vigorously for 20 minutes. After 2× extraction withethyl acetate, the combined organic extracts are washed with brine.After drying on sodium sulfate, and after the desiccant is suctioned offand the solvent is spun off, the residue is chromatographed on silicagel (mobile solvent ethyl acetate/hexane). 327.5 mg (62.8%) of thedesired imine is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.38 (3H), 1.58 (3H), 2.45 (1H), 2.71 (1H),2.99 (3H), 3.69 (3H), 4.75 (1H), 6.28 (1H), 6.79-6.90 (2H), 7.08 (1H),7.37-7.49 (2H), 9.63 (1H).

7-Chloro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

80 mg (0.165 mmol) of imine is dissolved in 1.2 ml of dichloromethane,mixed drop by drop with 0.5 ml of titanium tetrachloride at 0° C. andstirred for 1¾ hours at this temperature. The reaction mixture is mixeddrop by drop with saturated sodium bicarbonate solution at 0° C. andmixed with ethyl acetate. The cold bath is removed, and the batch isstirred vigorously for 20 minutes. After extraction with ethyl acetate,the combined organic extracts are worked up as usual. Afterchromatography on silica gel (mobile solvent methanol/dichloromethane),60.7 mg (75.8%) of the desired compound is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.40 (3H), 1.56 (3H), 1.99-2.15 (2H), 2.78(3H), 3.90 (3H), 5.40 (1H), 6.18 (1H), 6.72-6.90 (2H), 7.10-7.20 (2H),7.60 (1H), 9.79 (1H).

7-Chloro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol

35 mg (0.072 mmol) of the compound that is described in the precedingsection is mixed with 0.7 ml of a one-molar solution of boron tribromidein dichloromethane while being cooled in an ice bath, and it is stirredfor two hours while being cooled in an ice bath. The reaction mixture ismixed drop by drop at −30° C. with saturated sodium bicarbonatesolution, specifically to pH 8. The cold bath is removed, and the batchis stirred vigorously for 15 minutes at room temperature. After 2×extraction with ethyl acetate, the organic extracts are worked up asusual. After chromatography on silica gel (mobile solventmethanol/dichloromethane), 17.7 mg (52.2 mg) of the desired compound isultimately isolated.

¹H-NMR (300 MHz, CD₃OD): δ=1.40 (3H), 1.56 (3H), 2.07-2.20 (2H), 2.89(3H), 5.23 (1H), 6.83 (1H), 6.99 (1H), 7.20 (1H), 7.59 (1H), 9.69 (1H).

Example 1475-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-2H-isoquinolin-1-one5-[4-(4-Chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidenamino)-2H-isoquinolin-1-one

400 mg (1.232 mmol) of the4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal thatis described in the example above is reacted with 197.3 mg (1.232 mmol)of 5-amino-2H-isoquinolin-1-one to form imine. After the reaction,conventional working-up and chromatography, 332.9 mg (57.9%) of thedesired imine is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.38 (3H), 1.56 (3H), 2.43 (1H), 2.72 (1H),3.70 (3H), 4.95 (1H), 6.41 (1H), 6.75-6.98 (3H), 7.08-7.31 (2H),7.31-7.48 (2H), 11.2 (1H).

5-(7-Chloro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-ylamino-2H-isoquinolin-1-one

100 mg (0.214 mmol) of imine is reacted with titanium tetrachloride asdescribed in Example 146. 36.9 mg (36.9%) of the desired cyclic compoundis isolated, specifically as a diastereomer mixture in a 65:35 ratio.

MS (ES+): 467 (100%)

5-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-2H-isoquinolin-1-one

27 mg (0.058 mmol) of the ether that is described in the section aboveis reacted with boron tribromide as described in Example 146. After thereaction is carried out and after the conventional working-up, 19.9 mg(75.9%) of the desired compound is obtained, specifically as a uniformdiastereomer.

¹H-NMR (300 MHz, CD₃OD): δ=1.29 (3H), 1.43 (3H), 1.98-2.09 (2H), 5.00(1H), 6.75 (1H), 6.86 (1H), 6.93 (1H), 7.00-7.10 (2H), 7.29 (1H), 7.59(1H).

Example 1485-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-2-methyl-2H-phthalazin-1-one5-[4-(4-Chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidenamino)-2-methyl-2H-phthalazin-1-one

350 mg (1.078 mmol) of the above-described4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal isreacted with 251.8 mg (1.078 mmol) of5-amino-2-methyl-2H-phthalazin-1-one to form imine. After the reaction,conventional working-up and chromatography, 328.4 mg (63.2%) of thedesired imine is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.38 (3H), 1.58 (3H), 2.43 (1H), 2.72 (1H),3.70 (3H), 3.89 (3H), 4.70 (1H), 6.51 (1H), 6.80-6.89 (2H), 7.10 (1H),7.40 (1H), 7.63 (1H), 8.33 (1H), 8.42 (1H).

5-(7-Chloro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-2-methyl-2H-phthalazin-1-one

100 mg (0.207 mmol) of imine is cyclized with titanium tetrachloride indichloromethane as described in Example 146. 30.5 mg (30.5%) of thedesired compound is isolated, specifically as a diastereomer mixture.

MS (ES+): 482 (100%)

5-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-2-methyl-2H-phthalazin-1-one

24 mg (0.049 mmol) of the ether that is described in the section aboveis reacted with boron tribromide as described in Example 146. After thereaction is performed and after the conventional working-up, 18.7 mg(75.9%) of the desired compound is obtained, specifically as adiastereomer mixture.

MS (ES+): 468 (100%)

Example 1495-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-1H-quinolin-2-one5-[4-(4-Chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidenamino)-1H-quinolin-2-one

350 mg (1.078 mmol) of the4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal thatis described in the example above is reacted with 172.6 mg (1.078 mmol)of 5-amino-1H-quinolin-2-one to form imine. After reaction, conventionalworking-up and chromatography, 319.4 mg (6349%) of the desired imine isobtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.34 (3H), 1.55 (3H), 2.43 (1H), 2.70 (1H),3.70 (3H), 4.85 (1H), 6.00 (1H), 6.70-6.90 (3H), 7.13 (1H), 7.29-745(3H), 8.17 (1H), 12.30 (1H).

5-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-1H-quinolin-2one

106 mg (0.227 mmol) of imine is mixed at −20° C. with 2.3 ml of a 1 Msolution of boron tribromide in dichloromethane, and it is stirred fortwo hours at −20° C. to 0° C. The reaction mixture is brought to pH 8with saturated sodium bicarbonate solution and worked up as usual. Afterchromatography on silica gel (mobile solvent methanol/dichloromethane),55.1 mg (53.5%) of the desired cyclic compound is isolated as a freephenol.

¹H-NMR (300 MHz, CD₃OD): δ=1.41 (3H), 1.55 (3H), 2.05-2.20 (2H), 5.12(1H), 6.49-6.64 (2H), 6.73 (1H), 6.98 (1H), 7.16 (1H), 7.40 (1H), 8.25(1H).

Example 1507-Chloro-1-(2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol4-(4-Chloro-3-methoxyphenyl)-1,1,1-trifluoro-2-[(2-methylquinazolin-5-ylamino)-methyl]-4-methyl-pentan-2-ol

200 mg (0.616 mmol) of(rac.)-4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanalare reacted with 98.1 mg (0.616 mmol) of 5-amino-2-methylquinazoline, asdescribed in Example 146, to form imine. After the conventionalworking-up and purification, 184.3 mg (64.2%) of the desired imine isisolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.36 (3H), 1.59 (3H), 2.45 (1H), 2.73 (1H),2.93 (3H), 3.68 (3H), 4.82 (1H), 6.30 (1H), 6.78-6.90 (2H), 7.08 (1H),7.48 (1H), 7.71 (1H), 7.84 (1H), 9.60 (1H).

7-Chloro-1-(2-methylquinazolin-5-ylamino)-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

180 mg (0.386 mmol) of imine is cyclized as described with the aid oftitanium tetrachloride. 165.6 mg (92%) of the desired cyclic compound isisolated.

¹H-NMR (300 MHz, CD₃OD): δ=1.49 (3H), 1.61 (3H), 2.10-2.25 (2H), 2.84(3H), 3.93 (3H), 5.31 (1H), 6.95 (1H), 7.10 (1H), 7.19-7.27 (2H), 7.81(1H), 9.65 (1H).

7-Chloro-1-(2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol

50 mg (0.107 mmol) of the derivative that is described in the sectionabove is reacted with the aid of boron tribromide to form thecorresponding phenol. 30.2 mg (66.1%) of the desired compound isisolated.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.33 (3H), 1.48 (3H), 1.95-2.13 (2H), 2.72(3H), 5.39 (1H), 6.15 (1H), 6.80-6.95 (2H), 6.95-7.13 (3H), 7.69 (1H),9.72 (1H), 10.03 (1H).

Example 1517-Chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl]-1,2,3,4-tetrahydronaphthalene-2,6-diol4-(4-Chloro-3-methoxyphenyl)-1,1,1-trifluoro-2-[(7-fluoro-2-methylquinazolin-5-ylimino)-methyl]-4-methyl-pentan-2-ol

200 mg (0.616 mmol) of aldehyde is reacted with 109.1 mg (0.616) of5-amino-7-fluoro-2-methylquinazoline as already described several times.173 mg (58.1%) of the desired imine is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.39 (3H), 1.58 (3H), 2.47 (1H), 2.73 (1H),2.90 (3H), 3.72 (3H), 4.64 (1H), 6.17 (1H), 6.80-6.90 (2H), 7.09 (1H),7.40-7.50 (2H), 9.49 (1H).

7-Chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

170 mg (0.351 mmol) of the above-described imine is cyclized with 1.05ml (1.053 mmol) of titanium tetrachloride in dichloromethane. After theconventional working-up and subsequent chromatography, 168.4 mg (99%) ofthe desired cyclic compound is isolated as an ether.

¹H-NMR (300 MHz, CD₃OD): δ=1.49 (3H), 1.61 (3H), 2.20 (2H), 2.80 (3H),3.93 (3H), 5.33 (1H), 6.70-6.85 (2H), 7.10 (1H), 7.20 (1H), 9.57 (1H).

7-Chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol

50 mg (0.103 mmol) of the ether that is described in the section aboveis subjected as usual to ether cleavage with boron tribromide. After theworking-up and the conventional chromatography on silica gel (mobilesolvent methanol/dichloromethane), 32.2 mg (66.4%) of the desiredcompound is isolated.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.32 (3H), 1.49 (3H), 1.95-2.13 (2H), 2.70(3H), 5.48 (1H), 6.15 (1H), 6.79 (1H), 6.88 (1H), 6.95-7.16 (2H), 9.68(1H), 10.03 (1H).

Example 1527-Chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol4-(4-Chloro-3-methoxyphenyl)-1,1,1-trifluoro-2-[(7,8-difluoro-2-methylquinazolin-5-ylimino)-methyl]-4-methyl-pentan-2-ol

200 mg (0.616 mmol) of aldehyde is reacted with 120 mg (0.616) of5-amino-7,8-difluoro-2-methylquinazoline as already described severaltimes. 201.3 mg (65.1%) of the desired imine is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.38 (3H), 1.58 (3H), 2.46 (1H), 2.72 (1H),2.96 (3H), 3.72 (3H), 4.59 (1H), 6.28 (1H), 6.80-6.90 (2H), 7.10 (1H),7.46 (1H), 9.53 (1H).

7-Chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

200 mg (0.398 mmol) of the above-described imine is cyclized with 1.19ml (1.194 mmol) of titanium tetrachloride in dichloromethane. After theconventional working-up and subsequent chromatography, 163.6 mg (81.8%)of the desired cyclic compound is isolated.

¹H-NMR (300 MHz, CD₃OD): δ=1.48 (3H), 1.61 (3H), 2.19 (2H), 2.86 (3H),3.93 (3H), 5.30 (1H), 6.88 (1H), 7.09 (1H), 7.21 (1H), 9.62 (1H).

7-Chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol

50 mg (0.099 mmol) of the compound that is described in the sectionabove is subjected as usual to ether cleavage with boron tribromide.After working-up and purification on flash chromatography (mobilesolvent methanol/dichloromethane), 29.5 mg (60.7) of the desiredcompound is isolated.

¹H-NMR (300 MHz, DMSO-d₆): 1.32 (3H), 1.47 (3H), 1.95-2.12 (2H), 2.78(3H), 5.45 (1H), 6.13 (1H), 6.92-7.18 (4H), 9.73 (1H), 10.02 (1H).

Example 1534-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1,3-dihydroindol-2-one4-[4-(4-Chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidenamino]-1,3-dihydroindol-2-one

150 mg (0.462 mmol) of aldehyde is boiled with 102.7 mg (0.693 mmol) of4-amino-1,3-dihydroindol-2-one in xylene after addition of titaniumtetraisopropylate to the water separator as already described in theexamples above. After conventional working-up and chromatography, 119.3mg (56.7%) of the desired imine is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.35 (3H), 1.50 (3H), 2.49 (1H), 2.66 (1H),3.35-3.59 (2H), 3.75 (3H), 4.89 (1H), 5.98 (1H), 6.70-6.90 (3H),7.02-7.22 (2H), 7.33 (1H), 8.22 (1H).

4-(7-Chloro-2-hydroxy-6-methoxy-4,4-dim ethyl-2-(trifluoromethyl)-,2,3,4-tetrahydronaphthalen-1-ylamino)-1,3-dihydroindol-2-one

119 mg (0.261 mmol) of the above-described imine is cyclized as usual indichloromethane with 0.78 ml of titanium tetrachloride. After working-upand chromatography, 78.1 mg (65.6%) of the desired compound is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.42 (3H), 1.59 (3H), 2.00-2.20 (2H),3.23-3.49 (2H), 3.91 (3H), 5.03 (1H), 6.37 (1H), 6.48 (1H), 7.03 (1H),7.10 (1H), 7.29 (1H).

4-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronapthalen-1-ylamino)-1,3-dihydroindol-2-one

65 mg (0.143 mmol) of the ether that is described in the section aboveis mixed with 1.4 boron tribromide in dichloromethane. After working-upand chromatography, 45.4 mg (72.1%) of the desired phenol is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.39 (3H), 1.51 (3H), 1.98-2.20 (2H),3.25-3.50 (2H), 5.00 (1H), 6.37 (1H), 6.46 (1H), 6.93 (1H), 7.10 (1H),7.21 (1H).

Example 1548,8-Dimethyl-5-(naphthalen-1-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol1,1,1-Trifluoro-4-(2-methoxyphenyl)-4-methyl-2-(naphthalen-1-yliminomethyl)-pentan-2-ol

150 mg (0.517 mmol) of2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal isconverted into imine with 74 mg (0.517 mmol) of 1-naphthylamine intoluene with the aid of titanium tetraisopropylate. After working-up andchromatography, 166.7 mg (77.7%) of the desired imine is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.42 (3H), 1.59 (3H), 2.29 (1H), 3.57 (1H),3.88 (3H), 5.09 (1H), 6.10 (1H), 6.48 (1H), 6.79 (1H), 7.00 (1H), 7.10(1H), 7.22 (1H), 7.40 (1H), 7.47-7.58 (2H), 7.69 (1H), 7.80 (1H), 8.05(1H).

8,8-Dimethyl-5-(naphthalen-1-ylamino-6-(trifluoromethyl-5,6,7,8-tetrahydronaphthalene-1,6-diol

160.9 mg (0.387 mmol) of the above-described imine is treated as usualwith boron tribromide at 0° C., and after conventional working-up andchromatography on a Flashmaster, 100.9 mg (62.7%) of the desired cyclicphenol is produced.

¹H-NMR (300 MHz, CDCl₃): δ=1.60 (3H), 1.73 (3H), 2.00-2.28 (2H), 3.09(1H), 4.79 (1H), 5.02 (1H), 5.20 (1H), 6.62 (1H), 6.85-7.02 (3H),7.30-7.58 (4H), 7.73-7.90 (3H).

Example 1558,8-Dimethyl-5-(naphthalen-2-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol1,1,1-Trifluoro-4-(2-methoxyphenyl-4-methyl-2-(naphthalen-2-yliminomethyl)-pentan-2-ol

150 mg (0.517 mmol) of2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal isconverted into imine with 74 mg (0.517 mmol) of 2-naphthylamine intoluene with the aid of titanium tetraisopropylate. After working-up andchromatography, 192.8 mg (89.8%) of the desired imine is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (3H), 1.58 (3H), 2.20 (1H), 3.58 (1H),3.89 (3H), 5.09 (1H), 6.69 (1H), 6.80-6.90 (2H), 6.95 (1H), 7.05-7.18(2H), 7.38-7.53 (3H), 7.63-7.85 (3H).

8,8-Dimethyl-5-(naphthalen-2-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol

173.0 mg (0.416 mmol) of the above-described imine is treated as usualwith boron tribromide at 0° C., and after conventional working-up andchromatography on a Flashmaster, 132.6 mg (76.6%) of the desired cyclicphenol is produced.

¹H-NMR (300 MHz, CDCl₃): δ=1.60 (3H), 1.66 (3H), 2.00-2.24 (2H), 3.04(1H), 5.00 (1H), 5.09 (1H), 6.62 (1H), 6.92-7.10 (4H), 7.28 (1H), 7.40(1H), 7.60-7.78 (3H).

Example 1562-Chloro-5-(6-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol5-(4-(3-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylideneamino]-naphthalen-2-ol

200 mg (0.616 mmol) of2-hydroxy-4-(3-chloro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanalis reacted as usual with 98.1 mg (0.616 mmol) of 5-amino-2-naphthol toform imine. 185.1 mg (64.5%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.47 (3H), 1.62 (3H), 2.40 (1H), 3.23 (1H),4.00 (3H), 4.99 (1H), 5.15 (1H), 6.39 (1H), 6.49 (1H), 6.83 (1H), 7.00(1H), 7.05-7.20 (2H), 7.23-7.32 (2H), 7.52-7.63 (2H), 7.95 (1H).

2-Chloro-5-(6-hydroxynaphthalin-1-ylamino)-8,8-dimethy-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-1,6-diol

185.1 mg (0.397 mmol) of imine is cyclized with boron tribromide, asalready described several times. 146.9 mg (81.8%) of the desired phenolis isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.59 (3H), 1.70 (3H), 2.02-2.28 (2H), 3.00(1H), 4.75 (1H), 5.10-5.19 (2H), 5.95 (1H), 6.73 (1H), 6.88 (1H),7.00-7.12 (2H), 7.12-7.22 (2H), 7.34 (1H), 7.70 (1H).

Example 1572-Chloro-5-(5-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol5-(4-(3-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylideneamino]-naphthalen-1-ol

200 mg (0.616 mmol) of2-hydroxy-4-(3-chloro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanalis reacted as usual with 98.1 mg (0.616 mmol) of 5-amino-1-naphthol toform imine. 145.0 mg (50.5%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.45 (3H), 1.62 (3H), 2.40 (1H), 3.25 (1H),4.01 (3H), 5.01 (1H), 5.39 (1H), 6.46 (1H), 6.53 (1H), 6.80-6.91 (2H),7.02 (1H), 7.30-7.40 (2H), 7.59 (1H), 7.64 (1H), 8.10 (1H).

2-Chloro-5-(5-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-1,6-diol

145.0 mg (0.311 mmol) of imine is cyclized with boron tribromide, asalready described several times. 87.6 mg (62.3%) of the desired phenolis isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.58 (3H), 1.70 (3H), 2.05-2.28 (2H), 3.00(1H), 4.78 (1H), 5.15 (1H), 5.49 (1H), 5.95 (1H), 6.80-6.93 (3H), 7.10(1H), 7.29 (1H), 7.32-7.45 (2H), 7.68 (1H).

Example 1583-Chloro-5-(6-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol5-(4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylideneamino]-naphthalen-2-ol

200 mg (0.616 mmol) of2-hydroxy-4-(4-chloro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanalare reacted as usual with 98.1 mg (0.616 mmol) of 5-amino-2-naphthol toform imine. 113.0 mg (39.4%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.38 (3H), 1.58 (3H), 2.30 (1H), 3.40 (1H),3.85 (3H), 5.00 (1H), 5.15 (1H), 6.06 (1H), 6.50 (1H), 6.75 (1H), 6.99(1H), 7.05-7.20 (2H), 7.28 (1H), 7.45 (1H), 7.58 (1H), 7.93 (1H).

3-Chloro-5-(6-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-1,6-diol

113.0 mg (0.243 mmol) of imine is cyclized with boron tribromide, asalready described several times. 85.7 mg (78.2%) of the desired compoundis isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.55 (3H), 1.65 (3H), 2.01-2.23 (2H), 2.95(1H), 4.80 (1H), 5.10 (1H), 5.20 (1H), 5.48 (1H), 6.60-6.75 (2H), 6.93(1H), 7.09 (1H), 7.10-7.23 (2H), 7.35 (1H), 7.74 (1H).

Example 1592-Chloro-8,8-dimethyl-5-(pyridin-3-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol4-(3-Chloro-2-methoxyphenyl)-1,1,1-(trifluoromethyl)-4-methyl-(pyridin-3-yliminomethyl)-pentan-2-ol

200 mg (0.616 mmol) of2-hydroxy-4-(3-chloro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanalis reacted as usual with 57.9 mg (0.616 mmol) of 3-aminopyridine to formimine. 197.2 mg (79.9%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.43 (3H), 1.60 (3H), 2.28 (1H), 3.25 (1H),3.98 (3H), 4.70 (1H), 6.75 (1H), 6.95 (1H), 7.00-7.15 (2H), 7.23 (1H),7.58 (1H), 8.12 (1H), 8.49 (1H).

6-Chloro-5-methoxy-4,4-dimethyl-1-(pyridin-3-ylamino)-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol

190.0 mg (0.474 mmol) of imine is cyclized with titanium tetrachlorideas already described several times. 184.0 mg (96.8%) of the desiredcyclic compound is isolated as ether.

¹H-NMR (300 MHz, CD₃OD): δ=1.54 (3H), 1.62 (3H), 2.11 (2H), 3.95 (3H),5.05 (1H), 7.11 (1H), 7.15-7.28 (3H), 7.83 (1H), 8.09 (1H).

2-Chloro-8,8-dimethyl-5-(pyridin-3-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol

100 mg (0.249 mmol) of the above-described ether is treated as usualwith boron tribromide. After the conventional working-up andchromatography, 85.8 mg (88.9%) of the desired compound is isolated.

¹H-NMR (300 MHz, CD₃OD): δ=1.58 (3H), 1.69 (3H), 2.00-2.20 (2H), 5.00(1H), 6.89 (1H), 7.10-7.30 (3H), 7.81 (1H), 8.06 (1H).

Example 1601,6-Dihydroxy-8,8-dimethyl-5-(pyridin-3-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

50 mg of the2-chloro-8,8-dimethyl-5-(pyridin-3-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diolthat is described in Example 159 is dissolved in 0.12 ml of1-methy-2-pyrrolidinone and mixed with 12.6 mg (0.258 mmol) of sodiumcyanide and 28.2 mg (0.129 mmol) of nickel(II) bromide. The reactionmixture is brought to reaction in the microwave as described in theliterature (J. Org. Chem. 68, 9122 (2003) (200° C., 20 bar). Aftercooling, the reaction mixture is diluted with ethyl acetate and then asmall amount of water is added. The mixture is filtered over Extrelut(mobile solvent ethyl acetate). The solvent is spun off, and the residueis chromatographed on silica gel (mobile solventmethanol/dichloromethane). 9.4 mg (19.2%) of the desired nitrile isisolated.

MS (CI): 378 (100%); IR (KBr): 2228.

Example 1612-Chloro-8,8-dimethyl-5-(pyridin-4-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol4-(3-Chloro-2-methoxyphenyl)-1,1,1-(trifluoromethyl)-4-methyl-(pyridin-4-yliminomethyl)-pentan-2-ol

200 mg (0.616 mmol) of2-hydroxy-4-(3-chloro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanalis reacted as usual with 57.9 mg (0.616 mmol) of 4-aminopyridine to formimine. 167.9 mg (68.0%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.43 (3H), 1.60 (3H), 2.29 (1H), 3.26 (1H),4.00 (3H), 4.55 (1H), 6.59-6.65 (2H), 6.80 (1H), 7.01 (1H), 7.11 (1H),7.55 (1H), 8.46-8.55 (2H).

6-Chloro-5-methoxy-4,4-dimethyl-1-(pyridin-4-ylamino)-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol

160.0 mg (0.399 mmol) of imine is cyclized with titanium tetrachlorideas already described several times. 45.2 mg (28.2%) of the desiredcyclic compound is isolated as ether.

¹H-NMR (300 MHz, CD₃OD): δ=1.55 (3H), 1.69 (3H), 2.12 (2H), 3.98 (3H),5.28 (1H), 6.80-6.93 (2H), 6.99 (1H), 7.28 (1H), 7.98-8.20 (2H).

2-Chloro-8,8-dimethyl-5-(pyridin-4-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol

37 mg (0.092 mmol) of the above-described ether is treated as usual withboron tribromide. After the conventional working-up and chromatography,13.8 mg (38.6%) of the desired compound is isolated.

¹H-NMR (300 MHz, CD₃OD): δ=1.58 (3H), 1.70 (3H), 2.00-2.20 (2H), 5.19(1H), 6.70-6.89 (3H), 7.19 (1H), 7.90-8.20 (2H).

Example 1625-(2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-oneMethyl-3-isopropyl-2-methoxybenzoate

28 g (156.25 mmol) of 2-hydroxy-3-isopropylbenzoic acid is dissolved in280 ml of DMF and added in drops to a mixture of 47.5 g of potassiumcarbonate in 274 ml of DMF. After one more hour of stirring at roomtemperature, 21.4 ml (343.76 mmol) of iodomethane is added in drops, andthe mixture is stirred for one day at room temperature. Afteracidification with 10% sulfur acid to pH 3-4 (ice bath cooling), thereaction mixture is extracted four times with 500 ml each of methyltert-butyl ether. The combined organic extracts are washed with waterand with brine and dried on sodium sulfate. After the desiccant isfiltered off, the solvent is spun off, and the residue ischromatographed several times on silica gel (mobile solvent methyltert-butyl ether/hexane). 25.59 g (79.02%) of the desired compound isisolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.26 (6H), 3.42 (1H), 3.85 (3H), 3.96 (3H),7.15 (1H), 7.43 (1H), 7.65 (1H).

2-(3-Isopropyl-2-methoxyphenyl)-propan-2-ol

25.59 g (142.81 mmol) of methyl-3-isopropyl-2-methoxybenzoate isdissolved in 250 ml of tetrahydrofuran and added in drops to 114.25 ml(342.74 mmol) of methylmagnesium bromide (3M in diethyl ether). In thiscase, the temperature increases to 46° C. After three hours of stirringat room temperature, 625 ml of saturated ammonium chloride solution isadded in drops to the reaction mixture. After 3× extraction with methyltert-butyl ether, the combined organic extracts are washed with waterand brine and dried (sodium sulfate). The desiccant is filtered off, thesolvent is spun off, and the residue (28.16 g=95.15%) is incorporated incrude form into the next stage.

¹H-NMR (300 MHz, CDCl₃): δ=1.25 (6H), 1.63 (6H), 3.31 (1H), 3.90 (3H),4.78 (1H), 7.00-7.23 (3H).

Ethyl-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-oxo-pentanoate

15.3 ml (129.71 mmol) of tin tetrachloride is added in drops to amixture, cooled to −72° C., that consists of 28.16 g (135.19 mmol) of2-(3-isopropyl-2-methoxyphenyl)-propan-2-ol and 50.9 g (270.38 mmol) of2-trimethylsilanyloxy-acrylic acid ethyl ester in 420 ml ofdichloromethane. In this case, the temperature increased to −65° C.After 30 minutes of stirring in this temperature interval, the reactionmixture is poured into a mixture that consists of saturated sodiumcarbonate solution and dichloromethane (in each case 250 ml). After 30minutes of stirring at room temperature, the batch is transferred into aspherical separating funnel and a 1:1 mixture that consists of water anddichloromethane is added until a phase separation takes place. After theorganic phase is shaken with sodium carbonate, 1N HCl and water, it isdried with sodium sulfate. According to the conventional procedure, theresidue is chromatographed on silica gel (mobile solvent ethylacetate/hexane). 20.44 g (48.35%) of the desired compound is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.15-1.34 (9H), 3.28 (1H), 3.38 (2H), 3.78(3H), 4.09-4.21 (2H), 7.05 (1H), 7.10-7.19 (2H).

Ethyl-2-hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanoate

11.82 g (38.58 mmol) ofethyl-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-oxopentanoate and 6.58g (46.29 mmol) of (trifluoromethyl)trimethylsilane are dissolved in 70ml of tetrahydrofuran and mixed with 50 mg of tetrabutylammoniumfluoride trihydrate (slight temperature increase). Since after threehours, no complete reaction has yet taken place, the same amount oftetrabutylammonium fluoride-trihydrate is added once more. Afterstirring overnight, 12.17 g of tetrabutylammonium fluoride trihydrate isadded to cleave the silyl ether that is produced and thus to obtaindirectly free hydroxyl compound. The reaction mixture is diluted withmethyl tert-butyl ether, and the organic extract is washed with waterand brine. After drying (sodium sulfate), and after the desiccant isfiltered off and the solvent is filtered off, the residue ischromatographed several times on silica gel (mobile solvent ethylacetate/hexane). 11.04 g (76%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.13-1.32 (9H), 1.40-1.48 (6H), 2.48 (1H),2.72 (1H), 3.32 (1H), 3.57 (1H), 3.65-3.78 (1H), 3.85 (3H), 4.08-4.20(1H), 6.96-7.09 (2H), 7.18 (1H).

4-(3-Isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol

11.04 g (29.33 mmol) of the ester that is described in the section aboveis dissolved in 90 ml of diethyl ether and mixed at 2° C. in portionswith 2.23 g (58.66 mmol) of lithium aluminum hydride. After stirringovernight at room temperature, 50 ml of saturated sodium bicarbonatesolution is carefully added in drops while being cooled in an ice bath.After one hour of vigorous stirring at room temperature, it is extractedthree times with methyl tert-butyl ether. The combined organic extractsare worked up as usual, and the residue that remains after the solventis spun off is chromatographed on silica gel (mobile solvent ethylacetate/hexane). 7.15 g (72.9%) of the desired diol is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.25 (3H), 1.29 (3H), 1.50 (3H), 1.58 (3H),1.80 (1H), 2.23 (1H), 2.61 (1H), 2.83 (1H), 3.23-3.49 (3H), 3.89 (3H),7.09 (1H), 7.17-7.26 (2H).

2-Hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal

3.17 g (25.04 mmol) of oxalyl chloride is introduced into 83 ml ofdichloromethane and cooled to −78° C. At this temperature, 3.9 g (50.08mmol) of dimethyl sulfoxide, dissolved in 10 ml of dichloromethane, isadded in drops. After five minutes of stirring, 7.15 g (21.38 mmol) of4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol,dissolved in 21.4 ml of dichloromethane, is added. Then, the reactionmixture is stirred for two hours at this low temperature. 10.8 g (106.9mmol) of triethylamine is carefully added in drops, and the batch isthen stirred vigorously at room temperature for one hour. After water isadded and after stirring is done for another ten minutes, it isextracted twice with dichloromethane. The combined organic extracts arewashed with 1% sulfuric acid, saturated sodium bicarbonate solution andbrine. After drying, and after the solvent is spun off, the residue ischromatographed on silica gel (mobile solvent ethyl acetate/hexane).Finally, 5.93 g (83.44%) of the desired aldehyde is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.20 (3H), 1.32 (3H), 1.40-1.54 (6H), 2.22(1H), 3.30 (1H), 3.40 (1H), 3.59 (1H), 3.83 (3H), 6.95-7.07 (2H), 7.20(1H), 8.91 (1H).

5-[2-Hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentylidenamino]-2H-isoquinolin-1-one

147.3 mg (0.443 mmol) of the aldehyde that is described in the sectionabove is stirred overnight at room temperature with 71 mg (0.443 mmol)of 5-amino-2H-isoquinolin-1-one in 1.3 ml of glacial acetic acid. Thereaction mixture is drawn off three times with toluene, and the residueis chromatographed on a Flashmaster. 157 mg (75%) of the desired imineis isolated.

¹H-NMR (300 MHz, DMSO-d₆): δ=0.93 (3H), 1.19 (3H), 1.43 (3H), 1.55 (3H),2.18 (1H), 3.18 (1H), 3.29 (1H, half under the water of the DMSO), 3.75(3H), 6.19 (1H), 6.33 (1H), 6.63 (1H), 6.77 (1H), 6.89-6.99 (2H),7.16-7.32 (3H), 8.03 (1H), 11.33 (1H).

5-(2-Hydroxy-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one

157 mg of imine (0.331 mmol) is dissolved in 2.5 ml of dichloromethaneand mixed drop by drop at 0° C. with 0.95 ml (0.993 mmol) oftitanium(IV) chloride. After one hour of stirring at 0° C., the reactionmixture is mixed drop by drop with saturated sodium bicarbonate solutionand diluted with ethyl acetate. The cold bath is removed, and the batchis stirred vigorously for 30 minutes at room temperature. After 2×extraction with ethyl acetate, the organic extracts are treated asusual. After the residue is chromatographed on a Flashmaster, 108 mg(68.98%) of the desired cyclic compound is obtained as a racemate.

¹H-NMR (300 MHz, CD₃OD): δ=1.10-1.30 (6H), 1.55 (3H), 1.70 (3H), 2.13(2H), 3.39 (1H, under the signal of CH₃OH), 3.80 (3H), 5.19 (1H), 6.86(1H), 6.99-7.20 (4H), 7.39 (1H), 7.70 (1H).

5-(2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one

70 mg (0.147 mmol) of the above-described cyclic ether is mixed at roomtemperature with 1.5 ml of a 1 M solution of boron tribromide indichloromethane, and it is stirred for five hours at room temperature.The reaction mixture is mixed with pieces of ice. Saturated sodiumbicarbonate solution is carefully added in drops, specifically up to pH8. After the mixture is diluted with ethyl acetate, it is vigorouslystirred. After 2× extraction with ethyl acetate, the combined organicextracts are washed with water and brine and dried (sodium sulfate).After the solvent is filtered and spun off, the remaining residue ischromatographed on silica gel (mobile solvent methanol/dichloromethane).43.2 mg (63.6%) of the desired compound is isolated.

¹H-NMR (300 MHz, DMSO-d₆): δ=0.96-1.20 (6H), 1.52 (3H), 1.68 (3H),1.90-2.11 (2H), 3.30 (1H, half under the signal of the water), 5.29(1H), 5.91 (1H), 6.00 (1H), 6.70 (1H), 6.81 (1H), 6.97 (1H), 7.05 (1H),7.17 (1H), 7.25 (1H), 7.49 (1H), 8.09 (1H), 11.20 (1H).

Example 1635-(2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one5-[2-Hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-(trifluoromethyl)-pentylideneamino]-1H-quinolin-2-one

300 mg (0.903 mmol) of the2-hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanalthat is described in Example 162 is reacted with5-amino-1H-quinolin-2-one and worked up as described in the exampleabove. After chromatography on a Flashmaster, 372 mg (86.91%) of thedesired imine is isolated.

¹H-NMR (300 MHz, DMSO-d₆): δ=0.90 (3H), 1.18 (3H), 1.40 (3H), 1.54 (3H),2.15 (1H), 3.15 (1H), 3.29 (1H, half under the water of the DMSO), 3.75(3H), 5.90 (1H), 6.20 (1H), 6.53 (1H), 6.64 (1H), 6.85-6.98 (2H), 7.13(1H), 7.22-7.36 (2H), 8.09 (1H), 11.77 (1H).

5-(2-Hydroxy-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-1H-quinolin-2-one

120 mg (0.253 mmol) of the described imine is cyclized with titanium(IV)chloride in dichloromethane as described in Example 162. Afterworking-up and chromatography, 64.3 mg (53.6%) of the desired cycliccompound is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.10-1.30 (6H), 1.58 (3H), 1.71 (3H),2.00-2.20 (2H), 3.31 (1H), 3.80 (3H), 4.01 (1H), 5.09 (1H), 5.25 (1H),6.50-6.70 (3H), 7.00-7.12 (2H), 7.35 (1H), 8.01 (1H), 10.78 (1H).

5-(2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one

114 mg (0.240 mmol) of the described imine is cooled to −20° C. andmixed with 2.4 ml of a 1 M boron tribromide solution in dichloromethane.First, it is stirred for two hours at −20° C. to 0° C. and then for 30minutes at room temperature. The reaction mixture is mixed drop by dropat −20° C. with saturated sodium bicarbonate solution until a pH of 8 isreached. The cold bath is removed, and the batch is stirred vigorouslyat room temperature for 10 minutes. After the extraction with ethylacetate, the combined organic extracts are shaken as usual. After thesolvent is spun off, 48 mg of a mixture that consists of cyclic etherand the cyclic phenol is obtained. To obtain the uniform ether-cleavedcompound, the mixture is treated once again with 1.2 ml of borontribromide solution, but this time at room temperature (3½ hours ofstirring). After the conventional working-up already described, andafter chromatography on silica gel, 52.6 mg (92.9%) of the desiredcompound is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.10-1.30 (6H), 1.60 (3H), 1.72 (3H),2.00-2.20 (2H), 3.25 (1H), 5.15 (1H), 6.51 (1H), 6.63 (1H), 6.70 (1H),6.88 (1H), 7.01 (1H), 7.39 (1H), 8.24 (1H).

Example 1645-(7-Fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-16-diol1,1,1-Trifluoro-2-[(7-fluoro-2-methylquinazolin-5-ylimino)-methyl-]-4-(3-isopropyl-2-methoxy-phenyl)-4-methyl-pentan-2-ol

150 mg (0.451 mmol) of the aldehyde that is described in Example 162 isreacted with 79.9 mg (0.451 mmol) of7-fluoro-2-methylquinazolin-5-ylamine in xylene with the aid oftitanium(IV) isopropylate to form imine. After conventional working-up,207.8 mg (93.6%) of the desired compound is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=0.83 (3H), 1.20 (3H), 1.41 (3H), 1.62 (3H),2.25 (1H), 2.90 (3H), 3.20 (1H), 3.68 (1H), 3.83 (3H), 4.61 (1H), 5.95(1H), 6.54 (1H), 6.80 (1H), 6.99 (1H), 7.30-7.42 (2H), 9.30 (1H).

1-(7-Fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl-1,2,3,4-tetrahydronaphthalen-2-ol

207.8 mg (0.422 mmol) of the imine that is described in the sectionabove is cyclized with 1.26 ml of titanium(IV) chloride indichloromethane. According to the process that is described in Example162, 194.4 mg (93.5%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.10-1.30 (6H), 1.60 (3H), 1.75 (3H),2.10-2.28 (2H), 2.87 (3H), 3.33 (1H), 3.80 (3H), 4.99 (1H), 6.09 (1H),6.20 (1H), 6.54 (1H), 6.90 (1H), 7.06-7.19 (2H), 9.20 (1H).

(−)]-(7-Fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol(+)-1-(7-Fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl-1,2,3,4-tetrahydronaphthalen-2-ol

94 mg of the racemic compound is separated in the ether stage on achiral column to obtain the two enantiomers. 36 mg of the (−)-enantiomerand 32 mg of the (+)-enantiomer are isolated.

(−)-Enantiomer: [α]_(D)=−34.4° (c=1, CH₃OH); (+)-Enantiomer:[α]_(D)=+31.77° (c=1, CH₃OH)

5-(7-Fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol

100 mg (0.203 mmol) of1-(7-fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-diolis treated with BBr₃ in dichloromethane as already described severaltimes. After working-up and chromatography, 18.5 mg (19.1%) of thedesired phenol is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.05-1.30 (6H), 1.65 (3H), 1.74 (3H), 2.28(2H), 2.79 (3H), 3.27 (1H), 5.30 (1H), 6.65-6.90 (2H), 6.93-7.17 (2H),9.55 (1H).

(−)-5-(7-Fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol(+)-5-(7-Fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol

The enantiomer-pure ethers that are described above are converted intothe enantiomer-pure phenols as described for the racemate. 10.4 mg(43.5) of the phenol is obtained from 247 mg of ether ((−)-enantiomer).5.1 mg (19.6%) of the phenol is isolated from 26.7 mg of ether((+)-enantiomer).

Example 1655-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-16-diol1,1,1-Trifluoro-2-[(7,8-difluoro-2-methylquinazolin-5-ylimino)-methyl]-4-(3-isopropyl-2-methoxy-phenyl)-4-methyl-pentan-2-ol

150 mg (0.451 mmol) of the aldehyde that is described in Example 162 isreacted with 88 mg (0.451 mmol) of7,8-difluoro-2-methylquinazolin-5-ylamine in xylene with the aid oftitanium(IV) isopropylate to form imine. After the conventionalworking-up,

208.6 mg (90.7%) of the desired compound is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=0.90 (3H), 1.23 (3H), 1.43 (3H), 1.63 (3H),2.23 (1H), 2.98 (3H), 3.22 (1H), 3.69 (1H), 3.83 (3H), 4.58 (1H), 5.99(1H), 6.58 (1H), 6.88 (1H), 6.99 (1H), 7.39 (1H), 9.39 (1H).

1-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

208.6 mg (0.409 mmol) of the imine that is described in the sectionabove is cyclized with 1.23 ml of titanium(IV) chloride indichloromethane. According to the process that is described in Example162, 198 mg (95.9%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.10-1.30 (6H), 1.63 (3H), 1.76 (3H),2.09-2.25 (2H), 2.91 (3H), 3.32 (1H), 3.80 (3H), 4.94 (1H), 5.40 (1H),5.82 (1H), .6.58 (1H), 7.03-7.19 (2H), 9.27 (1H).

(−)-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol(+)-1-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

80 mg of the racemic compound is separated in the ether stage on achiral column to obtain the two enantiomers. 38.1 mg of (−)-enantiomerand 35.5 mg of (+)-enantiomer are obtained.

(−)-Enantiomer: [α]_(D)=−38.5° (c=1, CH₃OH); (+)-Enantiomer: [α]D+³⁷′(c=1, CH₃OH)

5-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl-5,6,7,8-tetrahydronaphthalene-1,6-diol

100 mg (0.196 mmol) of1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-olis treated with BBr₃ in dichloromethane as already described severaltimes. After working-up and chromatography, 33 mg (33.9%) of the desiredphenol is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.05-1.30 (6H), 1.63 (3H), 1.74 (3H), 2.12(2H), 2.83 (3H), 3.26 (1H), 5.38 (1H), 6.73-6.90 (2H), 7.03 (1H), 9.59(1H).

(−)-5-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol(+)-5-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl-5,6,7,8-tetrahydronaphthalene-1,6-diol

The above-described enantiomer-pure ethers are converted into theenantiomer-pure phenols as described for the racemate. 6.6 mg (22.9%) ofthe phenol is obtained from 29.7 mg of ether ((−)-enantiomer). 10.7 mg(40.6%) of the phenol is isolated from 27.1 mg of ether((+)-enantiomer).

Example 1665-(8-Fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol

1,1,1-Trifluoro-2-[(8-fluoro-2-methylquinazolin-5-ylimino)-methyl-]-4-(3-isopropyl-2-methoxy-phenyl)-4-methyl-pentan-2-ol

150 mg (0.451 mmol) of the aldehyde that is described in Example 162 isreacted with 79.9 mg (0.451 mmol) of8-fluoro-2-methylquinazolin-5-ylamine in xylene with the aid oftitanium(IV) isopropylate to form imine. After conventional working-up,176 mg (79.3%) of the desired compound is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=0.82 (3H), 1.20 (3H), 1.45 (3H), 1.62 (3H),2.25 (1H), 3.00 (3H), 3.20 (1H), 3.63 (1H), 3.83 (3H), 4.69 (1H), 6.20(1H), 6.47 (1H), 6.70 (1H), 6.98 (1H), 7.28-7.40 (2H), 9.48 (1H).

1-(8-Fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

176 mg (0.358 mmol) of the imine that is described in the section aboveis cyclized with 1.1 ml of titanium(IV) chloride in dichloromethane.According to the working-up and chromatography described in Example 162,147.3 mg (83.6%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.10-1.35 (6H), 1.60 (3H), 1.75 (3H),2.05-2.25 (2H), 2.93 (3H), 3.33 (1H), 3.80 (3H), 4.88 (1H), 5.02 (1H),5.52 (1H), 6.70 (1H), 7.00-7.18 (2H), 7.49 (1H), 9.35 (1H).

5-(8-Fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol

50 mg (0.102 mmol) of1-(8-fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl-1,2,3,4-tetrahydronaphthalen-2-olis treated with BBr₃ in dichloromethane as already described severaltimes. After working-up and chromatography, 13.7 mg (28.2%) of thedesired phenol is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.05-1.30 (6H), 1.65 (3H), 1.76 (3H),2.00-2.20 (2H), 2.88 (3H), 3.27 (1H), 5.25 (1H), 6.77-6.94 (2H), 7.00(1H), 7.59 (1H), 9.68 (1H).

Example 1674-(2,5-Dihydroxy-6-isopropyl-,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-13-dihydro-indol-2-one4-[2-Hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentylidenamino]-1,3-dihydro-indol-2-one

250 mg (0.903 mmol) of the2-hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanalthat is described in Example 162 is reacted with4-amino-1,3-dihydro-indol-2-one as described in the example above andworked up. After chromatography, 334.9 mg (92.2%) of the desired imineis isolated.

¹H-NMR (300 MHz, CDCl₃): δ=0.99 (3H), 1.25 (3H), 1.46 (3H), 1.54 (3H),2.20 (1H), 3.27 (1H), 3.42 (2H), 3.49 (1H), 3.84 (3H), 4.79 (1H), 5.90(1H), 6.68-6.82 (2H), 6.90-7.09 (3H), 8.28 (1H).

4-(2-Hydroxy-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1,3-dihydro-indol-2-one

230 mg (0.497 mmol) of the described imine is cyclized with titanium(IV)chloride in dichloromethane as described in Example 162. Afterworking-up and chromatography, 208.3 mg (90.5%) of the desired cyclizedcompound is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.10-1.30 (6H), 1.51 (3H), 1.66 (3H),1.96-2.16 (2H), 3.38 (3H, are below the methanol signal), 3.79 (3H),5.03 (1H), 6.33 (1H), 6.49 (1H), 7.00-7.20 (3H).

4-(2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1,3-dihydro-indol-2-one

50 mg (0.108 mmol) of the described ether is treated with BBr₃ solutionin dichloromethane. After the above-described working-up andchromatography, 35.6 mg (73.4%) of the desired compound is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.10-1.30 (6H), 1.61 (3H), 1.70 (3H),1.95-2.18 (2H), 3.27 (1H), 3.38 (2H, lie below the methanol signal),5.01 (1H), 6.33 (1H), 6.49 (1H), 6.89 (1H), 6.95-7.15 (2H).

The following compounds are synthesized analogously from thecorresponding aldehydes and amines.

Example 168cis-6-Chloro-1-[(7,8-difluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.58 (s, 3H), 1.72 (s, 3H), 2.14 (d, 1H),2.22 (d, 1H), 2.92 (s, 3H), 3.97 (s, 3H), 4.91 (d, 1H), 5.83 (d, 1H),6.55 (dd, 1H), 7.03 (d, 1H), 7.23 (d, 1H), 9.24 (s, 1H).

Example 169cis-1-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-7-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, CDCl₃): δ=2.24-2.34 (m, 2H), 2.86 (ddd, 1H), 2.91 (s,3H), 3.12 (ddd, 1H), 3.63 (s, 3H), 5.00 (d, 1H), 5.47 (d, 1H), 6.75 (dd,1H), 6.79 (d, 1H), 6.84 (s, 1H), 7.11 (d, 1H), 7.49 (dd, 1H), 9.35 (s,1H).

Example 170cis-6-Chloro-1-[(7,8-difluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CD₃OD): δ=1.60 (s, 3H), 1.72 (s, 3H), 2.16 (s, 2H),2.84 (s, 3H), 5.30 (s, 1H), 6.84 (d, 1H), 6.86 (dd, 1H), 7.17 (d, 1H),9.60 (s, 1H).

Example 171cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-6-fluoro-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CD₃OD): δ=1.61 (s, 3H), 1.72 (s, 3H), 2.14 (s, 2H),2.84 (s, 3H), 3.98 (s, 3H), 5.27 (s, 1H), 6.76-6.94 (m, 3H), 9.59 (s,1H).

Example 172cis-1-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,7-diol

¹H-NMR (300 MHz, CD₃OD): δ=2.16-2.35 (m, 2H), 2.81 (ddd, 1H), 2.85 (s,3H), 3.08 (ddd, 1H), 5.24 (s, 1H), 6.67 (dd, 1H), 6.78 (d, 1H), 6.89(dd, 1H), 7.02 (d, 1H), 7.59 (dd, 1H), 9.67 (s, 1H).

Example 173 2-Hydroxy-3-(1-phenylcyclohexyl)-2-(trifluoromethyl)propanal

12.6 g (45.9 mmol) of ethyl-2-oxo-3-(1-phenylcyclohexyl)-propionate(WO9854159) and 19.9 ml (138 mmol) of (trifluoromethyl)-trimethylsilanein 215 ml of THF are cooled to −70° C. and mixed with 8.6 ml of a 1molar tetrabutylammonium fluoride solution in THF. The reaction mixtureis allowed to heat over 18 hours to room temperature and then pouredinto saturated sodium chloride solution. It is extracted several timeswith ethyl acetate, washed with saturated sodium chloride solution,dried with sodium sulfate and concentrated by evaporation in a vacuum.After chromatographic purification on silica gel (hexane/ethyl acetate20%), 13.1 g ofethyl-2-hydroxy-3-(1-phenylcyclohexyl)-2-(trifluoromethyl)-propionate isobtained as a yellow oil. A solution of 3.33 g (87.7 mmol) of lithiumaluminum hydride in 173 ml of THF is added in drops to 13.1 g (38.1mmol) of ester in 174 ml of THF at 0° C., and it is stirred for 16 hoursat room temperature. 20 ml of saturated ammonium chloride solution iscarefully added to the batch at 0° C., and it is stirred vigorously for15 more minutes. It is extracted several times with ethyl acetate,washed with saturated sodium chloride solution, dried with sodiumsulfate and concentrated by evaporation in a vacuum. Afterchromatographic purification on silica gel (hexane/ethyl acetate0%-33%), 6.1 g of3-(1-phenyl-cyclohexyl)-2-(trifluoromethyl)-propane-1,3-diol isobtained. 15.7 ml (113 mmol) of triethylamine is added to 6.1 g (20.2mmol) of diol in 245 ml of dichloromethane and 79 ml of DMSO, and 13.8 g(87 mmol) of pyridine SO₃ complex is added in portions over 10 minutes.It is stirred for 3 hours, and saturated ammonium chloride solution isadded. The mixture is stirred for another 15 minutes, the phases areseparated, and it is extracted with dichloromethane. It is washed withwater and dried on sodium sulfate. The solvent is removed in a vacuum,and after chromatographic purification on silica gel (hexane/ethylacetate, 0-33%), the desired product is obtained quantitatively.

¹H-NMR (CDCl₃): δ=1.17-1.78 (m, 9H), 1.98-2.05 (m, 1H), 2.41 (d, 1H),3.46 (d, 1H), 3.66 (s, 1H), 7.18 (d, 2H), 7.24 (t, 2H), 7.31 (d, 1H),8.55 (s, 1H).

cis-4′-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclohexane-[1,1° (2′H)-naphthalen]-3′-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.25-1.85 (m, 9H), 1.97 (d, 1H), 2.11 (d,1H), 2.68 (d, 1H), 2.91 (s, 3H), 5.08 (d, 1H), 5.38 (d, 1H), 6.69 (dd,1H), 7.18 (t, 1H), 7.34 (d, 1H), 7.35 (t, 1H), 7.47 (dd, 1H), 7.56 (d,1H), 9.36 (s, 1H).

Example 174cis-4′-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-3,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclohexane-[1,1′(2′H)-naphthalen]-3′-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.25-1.90 (m, 9H), 1.93 (d, 1H), 2.02 (d,1H), 2.64 (d, 1H), 2.89 (s, 3H), 4.99 (d, 1H), 5.66 (d, 1H), 6.54 (dd,1H), 7.18 (t, 1H), 7.29 (d, 1H), 7.36 (t, 1H), 7.54 (d, 1H), 9.25 (s,1H).

Example 175cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CD₃OD): δ=1.58 (s, 3H), 1.70 (s, 3H), 2.13 (s, 2H),2.84 (s, 3H), 5.28 (s, 1H), 6.71-6.87 (m, 3H), 6.99 (t, 1H), 9.59 (s,2H).

Example 176Trans-1-[(7,8-Difluoro-2-methylquinazolin-5yl)amino]-6-fluoro-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (s, 3H), 1.54 (s, 3H), 2.05 (d, 1H),2.19 (d, 1H), 2.76 (s, 3H), 3.57 (br, 1H), 4.62 (d, 1H), 5.27 (d, 1H),6.54 (br, 1H), 6.90-6.97 (m, 2H), 7.07 (dd, 1H), 9.10 (s, 1H).

Example 177cis-5-3′,4′-Dihydro-3′-hydroxy-3′-(trifluoromethyl)-spiro]cyclohexane-1,1′(2′H)-naphthalen-4′-yl]amino}-quinolin-2(1H)-one

¹H-NMR (300 MHz, CD₃OD): δ=0.91 (m, 1H), 1.12 (m, 3H), 1.89 (d, 1H),2.44 (d, 1H), 5.29 (s, 1H), 6.51 (d, 1H), 6.67 (d, 1H), 6.71 (d, 1H),6.79 (d, 1H), 7.09 (t, 1H), 7.21 (t, 1H), 7.24 (d, 1H), 7.39 (t, 1H),8.24 (d, 1H).

Example 178cis-4′-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-3,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalen]-3′-ol

¹H-NMR (300 MHz, CD₃OD): δ=0.92-0.98 (m, 1H), 1.13-1.19 (m, 3H), 1.98(d, 1H), 2.40 (d, 1H), 2.85 (s, 3H), 5.36 (s, 1H), 6.81 (d, 1H), 6.91(dd, 1H), 7.10 (t, 1H), 7.23 (t, 1H), 7.28 (d, 1H), 7.59 (dd, 1H), 9.68(s, 1H).

Example 179cis-6-Chloro-1-[(8-fluoro-2-methyloquinazolin-5-yl)amino]-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol4-(3-Chloro-2-methoxyphenyl-2-hydroxy-4-methyl-2-(trifluoroethyl)-pentanal

1.0 g (3.35 mmol) ofethyl-4-(3-chloro-2-methoxyphenyl)-4-methyl-2-oxovalerate and 0.96 (5.0mmol) of (pentafluoroethyl)-trimethylsilane in 7 ml of THF are mixedwith 62 mg (0.67 mmol) of tetramethylammonium fluoride at −40° C. It isstirred for 2 hours at −25° C., then 1 ml of 1N hydrochloric acid isadded to the reaction mixture, and after 10 minutes, it is poured intowater. It is extracted several times with ethyl acetate, washed withsaturated sodium chloride solution, dried with sodium sulfate andconcentrated by evaporation in a vacuum. 1.44 g ofethyl-4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)-valerate,which is mixed in 14.5 ml of diethyl ether at 0° C. with 0.22 g (5.9mmol) of lithium aluminum hydride, is obtained, and it is stirred for 2hours at room temperature. The batch is poured into ice water, and it isvigorously stirred for 15 more minutes. It is filtered through Celite,extracted several times with diethyl ether, washed with saturated sodiumchloride solution, dried with sodium sulfate and concentrated byevaporation in a vacuum. After chromatographic purification on silicagel (hexane/ethyl acetate 0%-20%), 0.77 g of4-(3-chloro-2-methoxyphenyl)-2-(pentafluoroethyl)-4-methyl-propane-1,2-diolis obtained. 0.84 ml (6.1 mmol) of triethylamine and 388 mg (2.44 mmol)of pyridine SO₃ complex are added to 0.46 g (1.22 mmol) of diol in 9.5ml of dichloromethane and 2.5 ml of DMSO. It is stirred for 2 hours, andthen another 388 mg (2.44 mmol) of pyridine SO₃ complex is dosed in.After 1 hour of stirring, saturated ammonium chloride solution is added.The mixture is stirred for another 15 minutes, the phases are separated,and it is extracted with diethyl ether. It is washed with saturatedammonium chloride solution and dried on sodium sulfate. The solvent isremoved in a vacuum, and after chromatographic purification on silicagel (hexane/ethyl acetate, 30%), 357 g of product is obtained.

¹H-NMR (CDCl₃): δ=1.43 (s, 3H), 1.48 (s, 3H), 2.34 (d, 1H), 3.29 (d,1H), 3.58 (s, 1H), 4.01 (s, 3H), 6.95 (t, 1H), 7.05 (dd, 1H), 7.30 (dd,1H), 9.10 (s, 1H).

cis-6-Chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CD₃OD): δ=1.61 (s, 3H), 1.74 (s, 3H), 2.14 (d, 1H),2.20 (d, 1H), 2.86 (s, 3H), 5.34 (s, 1H), 6.84 (d, 1H), 6.86 (dd, 1H),7.12 (d, 1H), 7.57 (dd, 1H), 9.65 (s, 1H).

Example 180Cis-6-Chloro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CDCl₃): δ=1.58 (s, 3H), 1.72 (s, 3H), 2.17 (d, 1H),2.26 (d, 1H), 2.84 (s, 3H), 3.95 (s, 3H), 5.05 (d, 1H), 6.07 (d, 1H),6.51 (dd, 1H), 6.91 (dd, 1H), 7.04 (d, 1H), 7.18 (d, 1H), 9.17 (s, 1H).

Example 181Trans-6-Chloro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CD₃OD): δ=1.45 (s, 3H), 1.61 (s, 3H), 2.29 (d, 1H),2.37 (d, 1H), 2.74 (s, 3H), 3.65 (s, 3H), 5.58 (s, 1H), 6.83 (dd, 1H),6.98 (dd, 1H), 7.30 (dd, 1H), 7.42 (d, 1H), 9.52 (s, 1H).

Example 182cis-5-{[6-Chloro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

¹H-NMR (300 MHz, CDCl₃): δ=1.55 (s, 3H), 1.72 (s, 3H), 2.07 (d, 1H),2.20 (d, 1H), 3.96 (2, 3H), 5.12 (d, 1H), 5.46 (br, 1H), 5.81 (d, 1H),6.44-6.53 (m, 3H), 6.95 (d, 1H), 7.06 (d, 1H), 7.32 (t, 1H), 8.28 (d,1H), 9.92 (s, 1H).

Example 183cis-5-{[2,5-Dihydroxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

¹H-NMR (300 MHz, CDCl₃): δ=1.58 (s, 3H), 1.76 (s, 3H), 2.08 (d, 1H),2.24 (d, 1H), 2.63 (s, 1H), 5.11 (d, 1H), 5.54 (s, 1H), 5.85 (d, 1H),5.97 (s, 1H), 6.42 (d, 1H), 6.49 (d, 1H), 6.49 (d, 1H), 6.52 (d, 1H),7.00 (dd, 1H), 7.31 (t, 1H), 8.31 (d, 1H), 9.77 (s, 1H).

Example 184cis-7′-Fluoro-4′-[(8-fluoro-2-methylquinazolin-5-yl)-amino]-3′,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen]-3′-ol3-[1-(3-Fluoro-2-methoxyphenyl)-cyclohexyl]-2-hydroxy-2-(trifluoromethyl)propanal

385 ml of a 0.5 molar (182 mmol) solution ofbis-(trimethylsilyl)-potassium amide in toluene is added in drops at 0°C. to 26.5 g (184 mmol) of 2,6-difluoroanisole and 24 ml (198 mmol) ofcyclohexylcyanide in 500 ml of toluene. It is stirred for 18 hours atroom temperature and mixed with water while being cooled with ice, andthe solution is set at a pH of 4 with 4N hydrochloric acid.

The organic phase is separated, and the aqueous phase is extractedseveral times with diethyl ether. It is washed with brine, dried withsodium sulfate and concentrated by evaporation in a vacuum. Afterchromatographic purification on silica gel (hexane/ethyl acetate5%-10%), 28.5 g of 1-(3-fluoro-2-methyoxyphenyl)-cyclohexylnitrile isobtained. 27.5 g (118 mmol) of nitrile is slowly mixed in 430 ml oftoluene at −78° C. with 147 ml (176 mmol) of diisobutyl aluminum hydridesolution (20% in toluene), and after 3 hours at −78° C., 35 ml ofisopropanol was added in drops. It is allowed to heat to −5° C., and 600ml of a 10% aqueous tartaric acid solution is added. After dilution withether, it is vigorously stirred, the organic phase is separated, and theaqueous phase is extracted several times with ethyl acetate. It iswashed with brine, dried with sodium sulfate and concentrated byevaporation in a vacuum. 27.5 g of aldehyde is obtained as a yellow oil.A solution of 5.7 g (21.2 mmol) of 2-diethylphosphono-2-ethoxyaceticacid ethyl ester in 25 ml of tetrahydrofuran is mixed with 13.6 ml (27.2mmol) of a 2 M solution of lithium diisopropylamide intetrahydrofuran-heptane-toluene within 15 minutes while being cooledwith ice, and it is stirred for 20 minutes at 0° C. Within 30 minutes, asolution of 5 g (21.2 mmol) of1-(3-fluoro-2-methoxyphenyl)-cyclohexylformanal in 5 ml oftetrahydrofuran is added in drops at 0° C. After 16 hours at roomtemperature, ice water is added, and it is extracted several times withether. It is washed with saturated ammonium chloride solution, dried onsodium sulfate and concentrated by evaporation. The crude product issaponified with 6 g of sodium hydroxide in 100 ml of ethanol and 50 mlof water over 4 days at room temperature. 1.7 g of acid, which isstirred with 35 ml of 2N sulfuric acid and 7 ml of acetic acid at 90° C.over 30 hours, is obtained. After cooling, it is made basic withpotassium carbonate, washed with ether and acidified with hydrochloricacid. After extraction with ethyl acetate, washing with saturated sodiumchloride solution and removal of the solvent, 1.09 g of the crude ketoacid is obtained. 1.09 g (3.7 mmol) of3-{1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionic acid and0.45 ml of sulfuric acid (96%) are refluxed in 40 ml of ethanol for 2hours. The batch is concentrated by evaporation in a vacuum, the residueis added in ice water, and it is made basic with saturated sodiumbicarbonate solution. It is extracted several times with ethyl acetate,washed with saturated sodium chloride solution, dried (sodium sulfate)and concentrated by evaporation in a vacuum. After chromatographicpurification on silica gel (hexane/ethyl acetate 20%), 1.05 g ofethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionate isobtained.

1.05 g (3.3 mmol) ofethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclohexyl]-2-oxopropionate and0.74 ml (5 mmol) of (trifluoromethyl)-trimethylsilane in 7 ml of THF aremixed with 62 mg of tetramethylammonium fluoride at −40° C. It isstirred for 2 hours at −25° C., and then another 0.35 ml (2.4 mmol) of(trifluoromethyl)-trimethylsilane and 62 mg of tetramethylammoniumfluoride are added. After another 2 hours, 1 ml of 2N hydrochloric acidis added, and the reaction mixture is added to water. It is extractedseveral times with ethyl acetate, washed with saturated sodium chloridesolution, dried with sodium sulfate, and concentrated by evaporation ina vacuum. After chromatographic purification on silica gel (hexane/ethylacetate 10%-40%), 800 mg ofethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)-propionateis obtained as a yellow oil. This oil is mixed in 40 ml of diethyl etherat 0° C. with 150 g (4 mmol) of lithium aluminum hydride, and it isstirred for 2.5 more hours at room temperature. 20 ml of saturatedammonium chloride solution is carefully added at 0° C. to the batch, andit is vigorously stirred for 15 more minutes. It is extracted severaltimes with diethyl ether, washed with saturated sodium chloridesolution, dried with sodium sulfate and concentrated by evaporation in avacuum. After chromatographic purification on silica gel (hexane/ethylacetate 10%-1 5%), 630 g of3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-(trifluoromethyl)-propane-1,2-diolis obtained.

¹H-NMR (CDCl₃): δ=1.44-1.87 (m, 10H), 2.19-2.38 (m, 4H), 3.15-3.42 (br,2H), 3.96 (s, 3H), 6.9 (ddd, 1H), 7.01 (d, 1H), 7.16 (ddd, 1H).

1.6 ml (11 mmol) of triethylamine and, in portions over 10 minutes, 1.4g (70 mmol) of pyridine SO₃ complex are added to 700 mg (2 mmol) of diolin 20 ml of dichloromethane and 7.8 ml of DMSO. It is stirred for 3hours, and saturated ammonium chloride solution is added. The mixture isstirred for another 15 minutes, the phases are separated, and it isextracted with dichloromethane. It is washed with water and dried onsodium sulfate. The solvent is removed in a vacuum, and the desiredaldehyde is obtained quantitatively.

cis-7′-Fluoro-4′-[(8-fluoro-2-methylquinazolin-5-yl)-amino]-3′,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro]cyclohexane-1,1′(2′H)-naphthalen]-3′-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.25-1.85 (m, 8H), 2.00 (d, 1H), 2.44 (ddd,1H), 2.64 (ddd, 1H), 2.91 (s, 3H), 2.92 (d, 1H), 4.00 (s, 3H), 4.96 (d,1H), 5.41 (d, 1H), 6.66 (dd, 1H), 6.93 (dd, 1H), 7.04 (dd, 1H), 7.47(dd, 1H), 9.34 (s, 1H).

Example 185Cis-7′-Fluoro-4′-[(8-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalene]-3′,8′-diol

¹H-NMR (300 MHz, CD₃OD): δ=1.22-1.85 (m, 8H), 2.03 (d, 1H), 2.82 (ddd,1H), 2.85 (s, 3H), 2.91 (d, 1H), 3.05 (ddd, 1H), 5.22 (s, 1H), 6.80-6.95(m, 3H), 7.56 (dd, 1H), 9.65 (s, 1H).

Example 186cis-7′-Fluoro-4′-[(7-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclohexane-1,1°(2′ H)-naphthalen]-3′-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.25-1.90 (m, 10H), 2.17 (d, 1H), 2.34 (d,1H), 2.80 (s, 3H), 3.56 (s, 3H), 4.59 (d, 1H), 5.33 (d, 1H), 6.91 (dd,1H), 7.00 (dd, 1H), 7.10 (dd, 1H), 7.17 (dd, 1H), 9.03 (s, 1H).

Example 187cis-5-(7′-Fluoro-3′,4′-dihydro-3′-hydroxy-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen-4′-yl]amino}-quinolin-2(1H)-one

¹H-NMR (300 MHz, CDCl₃): δ=1.25-1.90 (m, 8H), 2.09 (d, 1H), 2.41 (ddd,1H), 2.60 (ddd, 1H), 2.90 (d, 1H), 3.99 (s, 3H), 4.85 (s, 1H), 5.00 (d,1H), 5.67 (d, 1H), 6.48-6.55 (m, 3H), 6.83 (dd, 1H), 6.96 (dd, 1H), 7.31(t, 1H), 8.22 (d, 1H), 9.79 (s, 1H).

Example 188cis-6-Chloro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4,-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CD₃OD): δ=1.61 (s, 3H), 1.74 (s, 3H), 2.18 (s, 2H),2.79 (s, 3H), 5.42 (s, 1H), 6.76-6.82 (m, 3H), 7.15 (d, 1H), 9.54 (s,1H).

Example 189cis-6-Chloro-1-[(2-methylquinazolin-5yl)amino]-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CD₃OD): δ=1.61 (s, 3H), 1.74 (s, 3H), 2.18 (s, 2H),2.82 (s, 3H), 5.40 (s, 1H), 6.84 (d, 1H), 6.95 (d, 1H), 7.10 (d, 1H),7.20 (d, 1H), 7.79 (t, 1H), 9.62 (s, 1H).

Example 190cis-5-{7′-Chloro-3,4′-dihydro-3′,8′-dihydroxy-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen-4′-yl]-amino}-quinolin-2(1H)-one

¹H-NMR (300 MHz, CD₃OD): δ=1.25-1.90 (m, 8H), 2.02 (d, 1H), 2.80 (ddd,1H), 2.91 (d, 1H), 3.05 (ddd, 1H), 5.12 (d, 1H), 5.51 (d, 1H), 6.59 (d,1H), 6.69 (d, 1H), 6.81 (dd, 1H), 6.986 (dd, 1H), 7.37 (t, 1H), 8.23 (d,1H).

Example 191cis-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-ol4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal

1.0 g (3.54 mmol) ofethyl-4-(3-fluoro-2-methoxyphenyl)-2-oxo-4-methyl-valerate and 0.98 g(5.1 mmol) of (pentafluoroethyl)-trimethylsilane in 7 ml of THF aremixed with 65 mg (0.7 mmol) of tetramethylammonium fluoride at −40° C.The reaction mixture is heated to −25° C. and stirred at thistemperature. After 4.5 hours, 1 ml of 2N hydrochloric acid is added, andthe reaction mixture is added to water. It is extracted several timeswith ethyl acetate, washed with saturated sodium chloride solution,dried on sodium sulfate, and concentrated by evaporation in a vacuum.1.65 g ofethyl-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)valerateis obtained as a crude product. The ester is mixed in 80 ml of diethylether at 0° C. with 300 mg (8 mmol) of lithium aluminum hydride andstirred for 3.5 more hours at room temperature. A little water iscarefully added to the batch at 0° C., and it is stirred vigorously for15 minutes. It is filtered through Celite, and the precipitate isrewashed thoroughly with ethyl acetate. The filtrate is dried withsodium sulfate and concentrated by evaporation in a vacuum. Afterchromatographic purification on silica gel (hexane/ethyl acetate10%-15%), 800 mg of4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-(pentafluoroethyl)pentane-1,2-diolis obtained. 1.8 ml (13 mmol) of triethylamine is added to 800 mg (2.2mmol) of diol in 25 ml of dichloromethane and 8.9 ml of DMSO, and 1.6 g(10 mmol) of pyridine SO₃.complex is added in portions over 10 minutes.It is stirred over 2.5 hours, and saturated ammonium chloride solutionis added. The mixture is stirred for another 15 minutes, the phases areseparated, and it is extracted with dichloromethane. It is washed withwater and dried on sodium sulfate. The solvent is removed in a vacuum,and the desired aldehyde is obtained quantitatively.

¹H-NMR (CDCl₃): δ=1.40 (s, 3H), 1.46 (s, 3H), 2.35 (d, 1H), 3.28 (d,1H), 3.60 (s, 1H), 4.02 (s, 3H), 6.86 (dd, 1H), 6.91 (ddd, 1H), 7.01(ddd, 1H), 9.14 (s, 1H).

cis-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, CDCl₃): δ=1.55 (s, 3H), 1.69 (s, 3H), 2.13 (d, 1H),2.20 (d, 1H), 2.92 (s, 3H), 3.97 (s, 3H), 5.08 (d, 1H), 5.41 (d, 1H),6.70 (dd, 1H), 6.90 (dd, 1H), 7.0 (dd, 1H), 7.48 (dd, 1H), 9.33 (s, 1H).

Example 192cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-6-fluoro-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, CD₃OD): δ=1.55 (s, 3H), 1.68 (s, 3H), 2.14 (d, 1H),2.21 (d, 1H), 2.84 (s, 3H), 3.97 (s, 3H), 5.39 (s, 1H), 6.88 (dd, 1H),6.98 (dd, 1H), 7.03 (dd, 1H), 9.59 (s, 1H).

Example 193cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-6-fluoro-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CDCl₃): δ=1.61 (s, 3H), 1.72 (s, 3H), 2.15 (d, 1H),2.22 (d, 1H), 2.91 (s, 3H), 5.00 (d, 1H), 5.61 (br, 1H), 5.71 (d, 1H),6.56 (dd, 1H), 6.83 (dd, 1H), 6.92 (dd, 1H), 9.24 (s, 1H).

Example 194cis-5-{[6-Fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

¹H-NMR (300 MHz, CDCl₃): δ=1.54 (s, 3H), 1.69 (s, 3H), 2.07 (d, 1H),2.17 (d, 1H), 3.97 (s, 3H), 4.58 (br, 1H), 5.10 (d, 1H), 5.45 (d, 1H),6.52-6.56 (m, 3H), 6.83 (dd, 1H), 6.94 (dd, 1H), 7.34 (t, 1H), 8.12 (d,1H), 10.11 (s, 1H).

Example 195cis-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CDCl₃): δ=1.61 (s, 3H), 1.72 (s, 3H), 2.15 (d, 1H),2.23 (d, 1H), 2.92 (s, 3H), 5.08 (d, 1H), 5.38 (d, 1H), 5.64 (br, 1H),6.70 (dd, 1H), 6.85 (dd, 1H), 6.90 (dd, 1H), 7.48 (dd, 1H), 9.33 (s,1H).

Example 196cis-4′-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-7′-fluoro-3′,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalen]-3′-olEthyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionate

396 ml of a 0.5 molar (198 mmol) solution ofbis-(trimethylsilyl)potassium amide in toluene is added in drops at 0°C. over 40 minutes to 26 g (180 mmol) of 2,6-difluoroanisole and 14.6 ml(198 mmol) of cyclopropylcyanide in 500 ml of toluene. It is stirred for18 hours at room temperature and mixed with water and 1 M sulfuric acidwhile being cooled with ice. The organic phase is separated, and theaqueous phase is extracted several times with ethyl acetate. It iswashed with brine, dried with sodium sulfate and concentrated byevaporation in a vacuum. After chromatographic purification on silicagel (hexane/ethyl acetate 10%-20%), 12.7 g of1-(3-fluoro-2-methoxyphenyl)-cyclopropylnitrile is obtained. 12.7 g(66.1 mmol) of the nitrile is slowly mixed in toluene at −78° C. with82.7 ml (99.2 mol) of diisobutyl aluminum hydride solution (20% intoluene), and after 3 hours at −78° C., 11.1 ml of isopropanal is addedin drops. It is allowed to heat to −5° C., and 150 ml of a 10% aqueoustartaric acid solution is added. After dilution with ether, it isvigorously stirred, the organic phase is separated, and the aqueousphase is extracted several times with ethyl acetate. It is washed withbrine, dried with sodium sulfate, and concentrated by evaporation in avacuum. 11.8 g of aldehyde is obtained as a yellow oil. A solution of16.3 g (60.7 mmol) of 2-diethylphosphono-2-ethoxyacetic acid ethyl esterin 60 ml of tetrahydrofuran is mixed within 20 minutes with 33.4 ml(66.8 mmol) of a 2 M solution of lithium diisopropylamide intetrahydrofuran-heptane-toluene while being cooled with ice, and it isstirred for 30 minutes at 0° C. Within 30 minutes, a solution of 11.8 g(60.7 mmol) of I in 61 ml of tetrahydrofuran is added in drops at 0° C.After 20 hours at room temperature, ice water is added and extractedseveral times with ether and ethyl acetate. It is washed with saturatedammonium chloride solution, dried on sodium sulfate and concentrated byevaporation. The crude product is saponified with 170 ml of 2 M sodiumhydroxide solution in 170 ml of ethanol over 15 hours at roomtemperature. 13.9 g of acid, which is stirred with 87 ml of 2N sulfuricacid at 90° C. over 16 hours, is obtained. After cooling, it is madebasic with potassium carbonate, washed with ether, and acidified withhydrochloric acid. After extraction with ethyl acetate, washing withsaturated sodium chloride solution and removal of the solvent, 10.2 g ofthe crude keto acid is obtained. 10.2 g (40.6 mmol) of3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionic acid and 4.5ml (85.3 mmol) of sulfuric acid (96%) are refluxed in 200 ml of ethanolfor 1 hour. The batch is concentrated by evaporation in a vacuum, theresidue is added to ice water and made basic with saturated sodiumbicarbonate solution. It is extracted several times with ethyl acetate,washed with saturated sodium chloride solution, dried (sodium sulfate)and concentrated by evaporation in a vacuum. After chromatographicpurification on silica gel (hexane/ethyl acetate 20%), 9.6 g ofethyl-3-[1-(3-fluoro-2-methoxyphennyl)-cyclopropyl]-2-oxopropionate isobtained.

¹H-NMR (CDCl₃): δ=0.90 (m, 4H), 1.29 (t, 3H), 3.09 (s, 2H), 3.99 (d,3H), 4.20 (q, 2H), 6.87 (ddd, 1H), 6.95 (dd, 1H), 7.07 (d, 1H), 9.26.

3-[(3-Fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)propanal

9.6 g (34.3 mmol) ofethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionate and34.5 ml (233 mmol) of (trifluoromethyl)-trimethylsilane in 343 ml of DMFare mixed with 46.9 g of cesium carbonate at 0° C. It is stirred for 2hours at 0° C. and then the reaction mixture is added to water. It isextracted several times with ethyl acetate, washed with saturated sodiumchloride solution, dried with sodium sulfate and concentrated byevaporation in a vacuum. After chromatographic purification on silicagel (hexane/ethyl acetate 10%-40%), 10.4 g ofethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)-propionateis obtained as a yellow oil. This oil is mixed in 297 ml of diethylether at 0° C. with 2.25 g (59.4 mmol) of lithium aluminum hydride, andit is stirred for 1 more hour at room temperature. 20 ml of saturatedammonium chloride solution is carefully added to the batch at 0° C., andit is stirred vigorously for 15 more minutes. It is extracted severaltimes with diethyl ether, washed with saturated sodium chloridesolution, dried with sodium sulfate and concentrated by evaporation in avacuum. After chromatographic purification on silica gel (hexane/ethylacetate 10%-50%), 5.6 g of3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-(trifluoromethyl)-propane-1,2-diolis obtained. 12. 4 ml (89 mmol) of triethylamine is added to 5.6 g (18.1mmol) of diol in 100 ml of dichloromethane and 61 ml of DMSO, and 11 g(70 mmol) of pyridine/SO₃ complex is added in portions over 10 minutes.It is stirred over 3 hours, and saturated ammonium chloride solution isadded. The mixture is stirred for another 15 minutes, the phases areseparated, and it is extracted with dichloromethane. It is washed withwater and dried on sodium sulfate. The solvent is removed in a vacuum,and after chromatographic purification on silica gel (hexane/ethylacetate, 0-50%), 5.9 g of product is obtained.

¹H-NMR (CDCl₃): δ=0.68-0.76 (m, 2H), 0.90-1.02 (m, 2H), 2.03 (d, 1H),2.91 (d, 1H), 3.85 (s, 1H), 4.03 (s, 3H), 6.80 (d, 1H), 6.87 (ddd, 1H),6.98 (dd, 1H), 9.26 (s, 1H).

cis-4′-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-7′-fluoro-3′,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalen]-3′-ol

¹H-NMR (300 MHz, CD₃OD): δ=0.83 (ddd, 1H), 0.99 (ddd, 1H), 1.42 (ddd,1H), 1.89 (ddd, 1H), 2.01 (d, 1H), 2.15 (d, 1H), 2.84 (s, 3H), 3.85 (s,3H), 5.19 (s, 1H), 6.65 (dd, 1H), 6.96 (dd, 1H), 7.04 (dd, 1H), 9.63 (s,1H).

Example 197cis-7′-Fluoro-3′,4′-dihydro-8′-methoxy-4′-[(2-methylquinazolin-5-yl)amino]-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalen]-3′-ol

¹H-NMR (300 MHz, CDCl₃): δ=0.82 (ddd, 1H), 1.00 (ddd, 1H), 1.54 (ddd,1H), 1.86 (ddd, 1H), 1.91 (d, 1H), 2.32 (d, 1H), 2.84 (s, 3H), 3.87 (s,3H), 5.08 (d, 1H), 5.78 (d, 1H), 6.67 (d, 1H), 6.88 (dd, 1H), 7.05 (dd,1H), 7.28 (d, 1H), 7.70 (t, 1H), 9.36 (s, 1H).

Example 198cis-7′-Fluoro-3′,4′-dihydro-4′-[(2-methylquinazolin-5-yl)amino]-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalene-3′,8′-diol

¹H-NMR (300 MHz, CD₃OD): δ=0.67 (ddd, 1H), 0.90 (ddd, 1H), 1.77 (ddd,1H), 1.93 (d, 1H), 2.12 (ddd, 1H), 2.21 (d, 1H), 2.81 (s, 3H), 5.28 (s,1H), 6.75-6.88 (m, 3H), 7.18 (d, 1H), 7.78 (t, 1H), 9.65 (s, 1H).

Example 199cis-4′-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-7′-fluoro-3′,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalene]-3′,8′-diol

¹H-NMR (300 MHz, CDCl₃): δ=0.71 (ddd, 1H), 0.91 (ddd, 1H), 1.81 (d, 1H),1.83-2.00 (m, 2H), 2.39 (d, 1H), 2.87 (s, 3H), 4.98 (d, 1H), 5.75 (d,1H), 6.49 (dd, 1H), 6.78-6.89 (m, 2H), 9.28 (s, 1H).

Example 200cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-5-fluoro-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, CD₃OD): δ=1.53 (s, 3H), 1.65 (s, 3H), 2.17 (s, 2H),2.84 (s, 3H), 3.85 (s, 3H), 5.32 (s, 1H), 6.87 (dd, 1H), 6.95 (dd, 1H),7.07 (d, 1H), 9.61 (s, 1H).

Example 201 cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-5-fluoro4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol

¹H-NMR (300 MHz, CD₃OD): δ=1.54 (s, 3H), 1.66 (s, 3H), 2.16 (s, 2H),2.84 (s, 3H), 3.98 (s, 3H), 5.29 (s, 1H), 6.78 (dd, 1H), 6.86 (dd, 1H),6.94 (dd, 1H), 9.60 (s, 1H).

Example 202cis-7′-Fluoro-4′-[(8-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)-spirofcyclopropane-1,1′(2′H)-naphthalene]-3′,8′-diol

¹H-NMR (300 MHz, CDCl₃): δ=0.71 (ddd, 1H), 0.93 (ddd, 1H), 1.79 (d, 1H),1.90-2.06 (m, 2H), 2.39 (d, 1H), 2.91 (s, 3H), 3.80 (br, 1H), 5.05 (d,1H), 5.39 (d, 1H), 5.48 (br, 1H), 6.65 (dd, 1H), 6.80-6.90 (m, 2H), 7.46(dd, 1H), 9.35 (s, 1H).

Example 203cis-7′-Fluoro-4′-[(7-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalene]-3′,8′-diol

¹H-NMR (300 MHz, CDCl₃): δ=1.20-2.10 (m, 10H), 2.10 (d, 1H), 2.47 (d,1H), 2.68 (s, 3H), 4.66 (d, 1H), 5.33 (d, 1H), 6.91 (d, 2H), 7.03 (dd,1H), 7.10 (dd, 1H), 9.01 (s, 1H).

Example 204cis-6-Chloro-5-methoxy-1-[(2-methylquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

¹H-NMR (300 MHz, CD₃OD): δ=1.56 (s, 3H), 1.69 (s, 3H), 2.16 (s, 2H),2.72 (s, 3H), 3.97 (s, 3H), 5.25 (s, 1H), 6.82 (d, 1H), 7.11 (d, 1H),7.20 (d, 1H), 7.32 (d, 1H), 7.36 (d, 1H), 7.55 (t, 1H), 8.45 (d, 1H).

Example 205cis-6-Chloro-1-[(2-methylquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CD₃OD): δ=1.61 (s, 3H), 1.73 (s, 3H), 2.12 (d, 1H),2.18 (d, 1H), 2.72 (s, 3H), 5.23 (s, 1H), 6.82 (d, 1H), 6.87 (d, 1H),7.11 (d, 1H), 7.31 (d, 1H), 7.35 (d, 11H), 7.55 (t, 0.1H), 8.45 (d, 1H).

Example 206cis-1-[(2-Methyl-1-quinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol-N-oxide

¹H-NMR (300 MHz, CD₃OD): δ=1.44 (s, 3H), 1.58 (s, 3H), 2.19 (s, 2H),2.76 (s, 3H), 5.35 (s, 1H), 7.00 (dd, 1H), 7.12 (t, 1H), 7.27-7.34 (m,2H), 7.45-7.52 (m, 2H), 7.71 (t, 1H), 7.96 (d, 1H), 8.29 (d, 1H).

Example 207cis-6-Chloro-1-[(2-methylquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diolN-oxide

75 mg of 70% meta-chloroperbenzoic acid is added to 84 mg (0.19 mmol) ofcis-6-chloro-1-[(2-methylquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diolin 8 ml of dichloromethane, and the solution is stirred over two hours.50 mg of solid sodium bicarbonate is added, and after 30 minutes, it ispoured into water. It is extracted with dichloromethane, washed withsaturated sodium chloride solution and dried on sodium sulfate. Afterconcentration by evaporation and chromatography on silica gel(hexane/ethyl acetate 0-100%), 58 mg of the title compound is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.61 (s, 3H), 1.73 (s, 3H), 2.13 (d, 1H),2.18 (d, 1H), 2.75 (s, 3H), 5.30 (s, 1H), 6.85 (d, 1H), 7.01 (d, 1H),7.13 (d, 1H), 7.48 (d, 1H), 7.70 (t, 1H), 7.96 (d, 1H), 8.27 (d, 1H).

Example 208cis-6-[(2-Methyl-quinolin-5-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphthol[1,2-d]-1,3-dioxol-7-olN-oxide

¹H-NMR (300 MHz, CDCl₃): δ=1.49 (s, 3H), 1.58 (s, 3H), 2.06 (d, 1H),2.20 (d, 1H), 2.61 (s, 3H), 5.08 (d, 1H), 5.62 (d, 1H), 5.99 (s, 2H),6.64 (d, 1H), 6.83 (d, 1H), 6.85 (d, 1H), 7.13 (d, 1H), 7.55 (t, 1H),7.96 (d, 1H), 8.03 (d, 1H).

Example 209cis-7′-Fluoro-4′-[(7-fluoro-2-methylquinazolin-5-yl)amino]-3,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalene]-3′,8′-diol

¹H-NMR (30 MHz, CD₃OD): δ=0.66 (ddd, 1H), 0.89 (ddd, 1H), 1.86 (ddd,1H), 1.93 (d, 1H), 2.10 (ddd, 1H), 2.22 (d, 1H), 2.78 (s, 3H), 5.26 (s,1H), 6.67 (dd, 1H), 6.75-6.82 (m, 2H), 6.87 (dd, 1H), 9.58 (s, 1H).

Example 210 cis-5-(7′-Fluoro-3′4′-dihydro-3′,8′-dihydroxy-3′-(trifluoromethyl)-spiro[cyclopropane-1,1°(2′ H)-naphthalen-4′-yl]-amino}-quinolin-2(1H)-one

¹H-NMR (300 MHz, CD₃OD): δ=0.66 (ddd, 1H), 0.90 (ddd, 1H), 1.71 (ddd,1H), 1.88 (d, 1H), 2.09 (ddd, 1H), 2.20 (d, 2H), 5.15 (s, 1H), 6.51-6.54(m, 2H), 6.70 (d, 1H), 6.79 (dd, 1H), 6.85 (dd, 1H), 7.36 (t, 1H), 8.25(d, 1H).

Example 211Cis-7′-Chloro-4′-[(7-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalene]-3′,8′-diol

¹H-NMR (300 MHz, CDCl₃): δ=0.70 (ddd, 1H), 0.91 (ddd, 1H), 1.70 (ddd,1H), 1.77 (d, 1H), 2.08 (ddd, 1H), 2.44 (d, 1H), 2.82 (d, 3H), 5.06 (d,1H), 5.77 (s, 1H), 5.88 (d, 1H), 6.44 (dd, 1H), 6.88 (d, 1H), 6.91 (dd,1H), 7.13 (d, 1H), 9.23 (s, 1H).

Example 212Cis-7′-Chloro-3′,4′-dihydro-4′-[(2-methylquinolin-5-yl)amino]-3′-(trifluoromethyl)-spiro[cyclopropane-1,1°(2′H)-naphthalene]-3′,8′-diol

¹H-NMR (300 MHz, CD₃OD): δ=0.68 (ddd, 1H), 0.91 (ddd, 1H), 1.69 (ddd,1H), 1.91 (d, 1H), 2.11 (ddd, 1H), 2.22 (d, 1H), 2.72 (s, 3H), 5.20 (s,1H), 6.70 (d, 1H), 6.78-6.85 (m, 2H), 7.30 (d, 1H), 7.36 (d, 1H), 7.53(t, 1H), 8.47 (d, 1H).

Example 213cis-7′-Chloro-3′,4′-dihydro-4′-[(2-methyl-quinolin-5-yl)amino]-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalene]-3′,8′-diolN-oxide

¹H-NMR (300 MHz, CD₃OD): δ=0.67 (ddd, 1H), 0.91 (ddd, 1H), 1.74 (ddd,1H), 1.91 (d, 1H), 2.10 (ddd, 1H), 2.23 (d, 1H), 2.75 (s, 3H), 5.25 (s,1H), 6.78 (dd, 1H), 6.84 (dd, 1H), 6.90 (d, 1H), 7.49 (d, 1H), 7.69 (t,1H), 7.95 (d, 1H), 8.30 (d, 1H).

Example 214cis-7′-Chloro-4′-[(7-fluoro-2-methylquinazolin-5-yl)amino]-3,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen]-3′-ol

¹H-NMR (300 MHz, CDCl₃): 1.20-1.85 (m, 8H), 2.05 (d, 1H), 2.44 (ddd,1H), 2.63 (ddd, 1H), 2.82 (s, 3H), 2.97 (d, 1H), 4.00 (s, 3H), 4.95 (d,1H), 5.92 (d, 1H), 6.49 (dd, 1H), 6.91 (dd, 1H), 7.04 (d, 1H), 7.22 (d,1H), 9.16 (s, 1H).

Example 215cis-7′-Chloro-4′-[(7-fluoro-2-methylquinazolin-5-yl)amino]-3,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclohexane-1.1′(2′H)-naphthalene]-3′,8′-diol

¹H-NMR (300 MHz, CDCl₃): δ=1.25-1.85 (m, 8H), 1.86 (d, 1H), 2.79 (ddd,1H), 2.82 (s, 3H), 2.93 (ddd, 1H), 2.97 (d, 1H), 4.95 (d, 1H), 5.85 (d,1H), 6.14 (s, 1H), 6.48 (dd, 1H), 6.89-6.93 (m, 2H), 7.19 (d, 1H), 9.19(s, 1H).

Example 216cis-7′-Chloro-3′,4′-dihydro-4′-[(2-methylquinazolin-5-yl)amino]-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′ (2′H)-naphthalene-3′,8′-diol

¹H-NMR (300 MHz, CD₃OD): δ=0.69 (ddd, 1H), 0.92 (ddd, 1H), 1.71 (ddd,1H), 1.95 (d, 1H), 2.13 (ddd, 1H), 2.20 (d, 1H), 2.81 (s, 3H), 5.29 (s,1H), 6.85 (d, 2H), 7.10 (d, 1H), 7.19 (d, 1H), 7.78 (t, 1H), 9.65 (d,1H).

Example 217(−)-2-Chloro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-1,6-dioland(+)-2-Chloro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-1,6-diol(−)-6-Chloro-1-(1H-indazol-4-ylamino)-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-oland(+)-6-Chloro-1-(1H-indazol-4-ylamino)-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

The racemic compound (324.2 mg) that was produced according to theprocess that is described in the examples above is separated into itsenantiomers in the ether stage on a chiral column (Chiralpak AD 20μ,eluant hexane/ethanol). 122.8 mg of the (−)-enantiomer and 147.1 mg ofthe (+)-enantiomer are obtained.

(−)-Enantiomer: [α]_(D)=−0.8 (c=1, MeOH)

(+)-Enantiomer: [α]_(D)=+1.0 (c=1, MeOH)

(−)-2-Chloro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-dioland(+)-2-Chloro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol

24 mg (21.4%) of the phenol is obtained from 115.8 mg of the(−)-enantiomer ether by ether cleavage with BBr₃.

91.5 mg (66.9%) of the phenol is obtained from 141.2 mg of the(+)-enantiomer ether by ether cleavage with BBr₃.

Example 2185-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}quinolin-2(1H)-one4-(2-Methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal

Analogously to Example 7, 687 mg ofethyl-4-(2-methoxyphenyl)-4-methyl-2-oxopentanoate (WO 00/32584) isreacted with 1 g of (pentafluoroethyl)trimethylsilane and 0.5 ml(tetrabutylammonium fluoride solution (1 M in THF)) in 18 ml of THF toform g ofethyl-4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)-pentanoate.450 mg of the obtained ester in 12 ml of diethyl ester is mixed inportions at 0° C. with 66 mg of lithium aluminum hydride. After stirringfor 11 hours, it is added to saturated bicarbonate solution and filteredthrough diatomaceous earth. The phases are separated, and the aqueousphase is extracted with ethyl acetate. The organic phase is washed withwater and brine, dried (Na₂SO₄) and concentrated by evaporation. 420 mgof diol is obtained as a yellow oil. 400 mg of the diol is oxidized tothe corresponding aldehyde with 0.11 ml of oxalyl chloride, 0.21 ml ofDMSO and 1 ml of triethylamine. It is washed with water and brine, driedwith sodium sulfate and concentrated by evaporation in a vacuum. Afterchromatography on silica gel (hexane/ethyl acetate 0->5%), 268 mg of thetitle compound is obtained as a yellow oil.

¹H-NMR (CDCl₃): δ=1.39 (s, 3H), 1.46 (s, 3H), 2.26 (d, 1H), 3.46 (d,1H), 3.88 (s, 3H), 6.77-6.95 (m, 2H), 7.11 (dd, 1H), 7.13-7.28 (m, 1H),8.95 (s, 1H)

5-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthlalen-1-yl]amino}-quinolin-2(1H)-one

Analogously to Example 10, the corresponding imine is produced startingfrom 180 mg of4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal and83 mg of 5-aminoquinolin-2-(1H)-one. 7 mg of the title compound isobtained by reaction of 70 mg of the imine with 58 mg of aluminumtrichloride in 1.5 ml of dichloromethane.

¹H-NMR (CD₃OD): δ=1.52 (s, 3H), 1.66 (s, 3H), 2.09 (d, 1H), 2.15 (d,1H), 3.85 (s, 3H), 5.27 (s, 1H), 6.51 (d, 1H), 6.62 (d, 1H), 6.70 (d,1H), 6.92 (d, 2H), 7.11 (dd, 1H), 7.38 (t, 1H), 8.23 (d, 1H)

Example 2195-{[6-Chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-methylquinolin-2(1H)-one5-Amino-6-methylquinolin-2(1H)-one

4.12 g of 2-chloro-6-methylquinoline (J. Med. Chem. 1992, pp. 2761-2768)is added at 0° C. to a solution that consists of 15 ml of 100% nitricacid and 2 ml of 96% sulfuric acid. After 4 hours at 0° C., it is addedto water, and the product is filtered off. 4.66 g of2-chloro-6-methyl-5-nitroquinoline is obtained as a beige solid. Thelatter is reacted for 80 hours at 100° C. in 46 ml of glacial aceticacid and 26 ml of water. The thus obtained6-methyl-5-nitroquinolin-2(1H)-one is filtered off from the reactionsolution. The 3.45 g of product that is obtained is reacted withhydrogen under normal pressure in methanol to palladium on activatedcarbon to form aniline. 2.89 g of the title compound is obtained as abeige solid.

¹H-NMR (DMSO): δ=2.08 (s, 3H), 5.56 (s, 2H), 6.25 (d, 1H), 6.42 (d, 1H),7.06 (d, 1H═, 8.18 (d, 1H), 11.32 (s, 1H)

5-{[6-Chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronapthalen-1-yl]amino}-6-methylquinolin-2(1H)-one

Analogously to Example 10, the corresponding imine is produced startingfrom 500 mg of4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 300 mg of 5-amino-6-methylquinolin-2(1H)-one. 10 mg of the titlecompound is obtained by reaction of 80 mg of the imine with 2.5 ml oftitanium tetrachloride solution (1 M in dichloromethane) in 4.3 ml ofdichloromethane.

¹H-NMR (DMSO): δ=1.57 (s, 3H), 1.68 (s, 3H), 1.87 (d, 1H), 2.12 (d, 1H),2.38 (s, 3H), 3.88 (s, 3H), 4.87 (d, 1H), 5.85 (d, 1H), 5.96 (d, 1H),6.62 (d, 1H), 6.81 (d, 1H), 7.11 (d, 1H), 7.44 (d, 1H), 8.42 (s, 1H),11.57 (s, 1H)

Example 2205-{[2,5-Dihydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1)-one

Analogously to Example 3, 19 mg of the title compound is obtainedstarting from 74 mg of the compound of Example 41 with 0.48 ml of BBr₃solution (1 M in dichloromethane) at 40° C.

¹H-NMR (CD₃OD): δ=1.53 (s, 3H), 1.65 (s, 3H), 2.01 (d, 1H), 2.10 (s,3H), 2.12 (d, 1H), 5.10 (s, 1H), 6.47-6.56 (m, 2H), 6.58-6.65 (m, 2H),6.69 (d, 1H), 7.39 (t, 1H), 8.22 (d, 1H)

Example 2215-{[2-Hydroxy-5-methoxy-2-(pentafluoroethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(11H)-one4-(2-Methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal

Analogously to the synthesis of4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)-pentanal,1.05 g of the title compound is obtained starting from 1.7 g ofethyl-4-(2-methoxy-4-methylphenyl)-4-methyl-2-oxopentanoate (Example 41)with 1.4 g of (pentafluoroethyl)trimethylsilane, subsequent reductionwith 344 mg of lithium aluminum hydride and ultimate oxidation underSwern conditions.

¹H-NMR (CDCl₃): δ=1.36 (s, 3H), 1.42 (s, 3H), 2.23 (d, 1H), 2.32 (s,3H), 3.48 (d, 1H), 3.64 (s, 1H), 3.87 (s, 3H), 6.67 (s, 1H), 6.71 (d,1H), 6.97 (d, 1H), 8.93 (s, 1H)

5-{[2-Hydroxy-5-methoxy-2-(pentafluoroethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

Analogously to Example 10, the corresponding imine is produced startingfrom 200 mg of4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanaland 93 mg of 5-aminoquinolin-2(1H)-one. 2 mg of the title compound isobtained by reaction of 80 mg of the imine with 1.6 ml of titaniumtetrachloride solution (1 M in dichloromethane) in 5 ml ofdichloromethane.

¹H-NMR (CD₃OD): δ=1.48 (s, 3H), 1.62 (s, 3H), 2.05 (d, 1H), 2.12 (d,1H), 2.16 (s, 3H), 3.83 (s, 3H), 5.21 (s, 1H), 6.52 (d, 1H), 6.62 (d,1H), 6.71 (d, 1H), 6.75 (s, 2H), 7.40 (t, 1H), 8.23 (d, 1H)

Example 2225-{[2-Hydroxy-5-methoxy-2-(trifluoromethyl)-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-oneEthyl-4-(2-methoxy-3-methylphenyl)-4-methyl-2-oxopentanoate

Analogously to Example 7, methyl-2 methoxy-3-methylbenzoate is producedfrom 30 g of 3-methylsalicylic acid and 60 ml of methyl iodide with 125g of potassium carbonate in 640 ml of DMF. The ester is reacted byreaction with 129 ml of methyl magnesium chloride (3 M in THF) in 435 mlof THF to form 1-(2-methoxy-4-methylphenyl)-1-methylethanol. 20.8 g ofthe product that is obtained is reacted with 27.1 g of2-(trimethylsilyloxy)-acrylic acid ethyl ester in 410 ml ofdichloromethane at 0° C. with 10.4 ml of tin tetrachloride to form 12.63g of the title compound.

¹H-NMR (300 MHz, CDCl₃): δ=1.28 (t, 3H), 1.48 (s, 6H), 2.29 (s, 3H),3.37 (s, 2H), 3.76 (s, 3H), 4.14 (q, 2H), 6.95 (t, 1H), 7.05 (d, 1H),7.13 (d, 1H)

4-(2-Methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal

Analogously to Example 7, 14.68 g ofethyl-4-(2-methoxy-4-methylphenyl)-4-methyl-2-oxopentanoate is reactedwith 21.6 ml (trifluoromethyl)trimethylsilane and 9.7 ml oftetrabutylammonium fluoride solution (1 M in THF) in 195 ml of THF toform 13.73 g ofethyl-4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoate.The product is reduced with 2.84 g of lithium aluminum hydride in 560 mlof diethyl ether to form 11.62 g of4-(2-methoxy-4-methylphenyl-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol.The oxidation of the diol is carried out analogously to Example 7 underSwern conditions with 3.8 ml of oxalyl chloride, 7.1 ml of DMSO and 26.5ml of triethylamine to 5.91 g of the title compound.

¹H-NMR (CDCl₃): δ=1.44 (s, 3H), 1.48 (s, 3H), 2.22 (d, 1H), 3.36 (d,1H), 3.83 (s, 3H), 6.90-7.12 (m, 3H), 8.93 (s, 1H)

5-{[2-Hydroxy-5-methoxy-2-(trifluoromethyl)-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one

Analogously to Example 10, the corresponding imine is produced startingfrom 600 mg of4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 315 mg of 5-aminoquinolin-2(1H)-one. 12 mg of the title compound isobtained by reaction of 370 mg of the imine with 8.3 ml of titaniumtetrachloride (1 M in dichloromethane) in 20 ml of dichloromethane.

¹H-NMR (CD₃OD): δ=1.52 (s, 3H), 1.67 (s, 3H), 2.10 (s, 2H), 2.30 (s,3H), 3.79 (s, 3H), 5.16 (s, 1H), 6.51 (d, 1H), 6.61 (d, 1H), 6.70 (d,1H), 7.00 (s, 2H), 7.38 (t, 1H), 8.21 (d, 1H)

Examples 223 and 2244-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalideand4-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide

Analogously to Example 10, the corresponding imine is produced startingfrom 600 mg of4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and308 mg of 4-aminophthalide. By reaction of 640 mg of the imine with 7.7ml of bromine tribromide solution (1 M in dichloromethane), 165 mg of4-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalideis obtained as fraction 1, and 115 mg of4-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalideis obtained as fraction 2.

Fraction 1: ¹H-NMR (CDCl₃): δ=1.40 (s, 3H), 1.49 (s, 3H), 2.03 (d, 1H),2.13 (d, 1H), 3.17 (d, 1H), 3.32 (s, 1H), 3.90 (s, 3H), 5.01 (d, 1H),5.11-5.24 (m, 2H), 6.66 (d, 1H), 7.03 (d, 1H), 7.21-7.32 (m, 2H),7.39-7.50 (m, 2H)

Fraction 2: ¹H-NMR (CD₃OD): δ=1.55 (s, 3H), 1.67 (s, 3H), 2.04 (d, 1H),2.12 (d, 1H), 5.15 (s, 1H), 5.21 (d, 1H), 5.32 (d, 1H), 6.70 (d, 1H),6.84 (d, 1H), 6.96 (t, 1H), 7.07 (d, 1H), 7.18 (d, 1H), 7.42 (t, 1H)

Examples 225 and 226(−)-4-[4,4-Dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalideand(+)-4-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalideSeparation of(+/−)4-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (95:5,vvv). The

(−)-enantiomer: MS (EI): M⁺=421, [α]_(D)−79.3° (c=0.9, CHCl₃) and the

(+)-enantiomer: MS (EI): M⁺=421

are thus obtained.

Examples 227 and 228(−)-4-[2,5-Dihydroxy-4-4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalideand(+)-4-{[2,5-Dihydroxy-4-4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino}-phthalide Separation of(+/−)-4-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10,vvv). The (−)-enantiomer: MS (EI): M⁺=407, [α]_(D)−66.0° (c=1.0, CHCl₃)and the (+)-enantiomer: MS (EI): M⁺=407 are thus obtained.

Example 2295-{[5-Methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one

Analogously to Example 10, the corresponding imine is produced startingfrom 500 mg of4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanaland 288 mg of 5-amino-2-methylphthalazin-1-one. As in Example 3, 90 mgof the imine is reacted by reaction with 0.4 ml of titaniumtetrachloride (1 M in dichloromethane) in 5 ml of dichloromethane, and25 mg of the title compound is obtained.

¹H-NMR (DMSO): δ=1.42 (s, 3H), 1.57 (s, 3H), 1.95 (d, 1H), 2.05 (d, 1H),2.14 (s, 3H), 3.70 (s, 3H), 3.80 (s, 3H), 5.38 (d, 1H), 5.98 (s, 1H),6.57 (d, 1H), 6.66 (s, 1H), 6.80 (s, 1H), 7.25 (d, 1H), 7.47 (d, 1H),7.58 (t, 1H), 8.63 (s, 1H)

Examples 230 and 231(−)-5-{[5-Methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-oneand(+)-5-{[5-Methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-oneSeparation of(+/−)-5-{[5-methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with ethanol as an eluant. The

(−)-enantiomer: MS (EI): M⁺=461, and the

(+)-enantiomer: MS (EI): M⁺=461, [α]_(D)+4.9° (c=0.7, CHCl₃) are thusobtained.

Example 2325-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalin-1-yl]amino}-2-methylphthalazin-1-one

Analogously to Example 10, the corresponding imine is produced startingfrom 1.0 g of4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 542 mg of 5-amino-2-methyl-phthalazin-1-one. As in Example 3, 840 mgof the imine is reacted by reaction with 43.6 ml of titaniumtetrachloride (1 M in dichloromethane) in 40 ml of dichloromethane, and114 mg of the title compound is obtained.

¹H-NMR (DMSO): δ=1.47 (s, 3H), 1.61 (s, 3H), 2.00 (d, 1H), 2.14 (d, 1H),3.71 (s, 3H), 3.88 (s, 3H), 5.46 (d, 1H), 6.17 (s, 1H), 6.61 (d, 1H),7.00 (d, 1H), 7.27 (d, 1H), 7.33 (d, 1H), 7.49 (d, 1H), 7.60 (t, 1H),8.64 (s, 1H)

Examples 233 and 234(−)-5-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-oneand(+)-5-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-oneSeparation of(+/−)-5-{[6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10,vvv). The

(−)-Enantiomer: MS (EI): M⁺=481/483 and the

(+)-Enantiomer: MS (EI): M⁺=481/483, [α]_(D)+10.6° °(c=0.8 CHCl₃) arethus obtained.

Example 2355-{[6-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-amino}-2-methylphthalazin-1-one

Analogously to Example 3, 19 mg of the title compound is obtainedstarting from 20 mg of5-{[6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-onewith 0.13 ml of BBr₃ solution (1 M in dichloromethane) at 40° C.

¹H-NMR (DMSO): δ=1.52 (s, 3H), 1.65 (s, 3H), 2.00 (d, 1H), 2.11 (d, 1H),3.70 (s, 3H), 5.42 (d, 1H), 6.07 (s, 1H), 6.58 (d, 1H), 6.74 (d, 1H),7.20 (d, 1H), 7.26 (d, 1H), 7.47 (d, 1H), 7.58 (t, 1H), 8.63 (s, 1H),9.09 (s, 1H)

Example 236(−)-5-{[6-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino}-amino}-2-methylphthalazin-1-one

Analogously to Example 3, 23 mg of the title compound is obtainedstarting from 26 mg of(−)-5-{[6-chloro-4,4-dimethyl-5-(methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-onewith 0.5 ml of BBr₃ solution (1 M in dichloromethane) in 0.25 ml ofdichloromethane at 40° C.

¹H-NMR (DMSO): δ=1.52 (s, 3H), 1.65 (s, 3H), 2.00 (d, 1H), 2.11 (d, 1H),3.70 (s, 3H), 5.42 (d, 1H), 6.07 (s, 1H), 6.58 (d, 1H), 6.74 (d, 1H),7.20 (d, 1H), 7.26 (d, 1H), 7.47 (d, 1H), 7.58 (t, 1H), 8.63 (s, 1H),9.09 (s, 1H)

Example 237(+)-5-{[6-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-amino}-2-methylphthalazin-1-one

Analogously to Example 3, 12 mg of the title compound is obtainedstarting from 20 mg of(+)-5-{[6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-onewith 0.4 ml of BBr₃ solution (1 M in dichloromethane) in 0.25 ml ofdichloromethane at 40° C.

¹H-NMR (DMSO): δ=1.52 (s, 3H), 1.65 (s, 3H), 2.00 (d, 1H), 2.11 (d, 1H),3.70 (s, 3H), 5.42 (d, 1H), 6.07 (s, 1H), 6.58 (d, 1H), 6.74 (d, 1H),7.20 (d, 1H), 7.26 (d, 1H), 7.47 (d, 1H), 7.58 (t, 1H), 8.63 (s, 1H),9.09 (s, 1H)

Example 238(+)-5-{[2,5-Dihydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-amino}-2-methylphthalazin-1-one

Analogously to Example 3, 19 mg of the title compound is obtainedstarting from 20 mg of5-{[5-methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-onewith 0.13 ml of BBr₃ solution (1 M in dichloromethane) at 40° C.

¹H-NMR (DMSO): δ=1.46 (s, 3H), 1.60 (s, 3H), 1.94 (d, 1H), 2.01 (d, 1H),2.06 (s, 3H), 3.70 (s, 3H), 5.35 (d, 1H), 5.92 (s, 1H), 6.51 (s, 1H),6.53-6.63 (m, 2H), 7.26 (d, 1H), 7.46 (d, 1H), 7.57 (t, 1H), 8.63 (s,1H), 9.31 (s, 1H)

Example 2395-{[5-Methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one

Analogously to Example 10, the corresponding imine is produced startingfrom 600 mg of4-(3-methyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 316 mg of 5-amino-2-methylphthalazin-1-one. As in Example 3, 460 mgof the imine is reacted by reaction with 5.2 ml of titaniumtetrachloride (1 M in dichloromethane) in 23 ml of dichloromethane, and36 mg of title compound is obtained.

¹H-NMR (DMSO): δ=1.45 (s, 3H), 1.60 (s, 3H), 1.96 (d, 1H), 2.10 (d, 1H),2.24 (s, 3H), 3.70 (s, 3H), 3.72 (s, 3H), 5.40 (d, 1H), 6.03 (s, 1H),6.57 (d, 1H), 6.87 (d, 1H), 7.03 (d, 1H), 7.25 (d, 1H), 7.46 (d, 1H),7.58 (t, 1H), 8.63 (s, 1H).

Example 2405-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-one

Analogously to Example 10, the corresponding imine is produced startingfrom 1.0 g of4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 494 mg of 5-amino-phthalazin-1-one. As in Example 3, 775 mg of theimine is reacted by reaction with 24.9 ml of titanium tetrachloride (1 Min dichloromethane) in 46 ml of dichloromethane, and 483 mg of the titlecompound is obtained.

¹H-NMR (DMSO): δ=1.47 (s, 3H), 1.61 (s, 3H), 1.99 (d, 1H), 2.13 (d, 1H),3.88 (s, 3H), 5.45 (d, 1H), 6.17 (s, 1H), 6.57 (d, 1H), 7.00 (d, 1H),7.28 (d, 1H), 7.33 (d, 1H), 7.46 (d, 1H), 7.57 (t, 1H), 8.61 (s, 1H),1.256 (s, 1H)

Examples 241 and 242(−)-5-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalin-1-yl]amino}-phthalazin-1-oneand(+)-5-[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalin-1-yl]amino}-phthalazin-1-oneSeparation of(+/−)-5-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-one

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10,vvv). The

(−)-enantiomer: flash point=267-270° C., and the

(+)-enantiomer: flash point=263-265° C., [α]_(D)+6.5° °(c=1.2, CHCl₃)are thus obtained.

Example 2435-{[6-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-amino}-phthalazin-1-one

Analogously to Example 3, 19 mg of the title compound is obtainedstarting from 20 mg of5-{[6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-onewith 0.13 ml of BBr₃ solution (1 M in dichloromethane) at 40° C.

¹H-NMR (DMSO): δ=1.43 (s, 1H), 1.56 (s, 3H), 1.91 (d, 1H), 2.01 (d, 1H),5.33 (d, 1H), 6.00 (s, 1H), 6.44 (d, 1H), 6.65 (d, 1H), 7.12 (d, 1H),7.18 (d, 1H), 7.36 (d, 1H), 7.49 (t, 1H), 8.52 (s, 1H), 9.02 (s, 1H),12.46 (s, 1H)

Example 244(−)-5-{[6-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-amino}-2-methylphthalazin-1-one

Analogously to Example 3, 94 mg of the title compound is obtainedstarting from 100 mg of(−)-5-{[6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-onewith 2.1 ml of BBr₃ solution (1 M in dichloromethane) in 1 ml ofdichloromethane at 40° C.

¹H-NMR (DMSO): δ=1.43 (s, 1H), 1.56 (s, 3H), 1.91 (d, 1H), 2.01 (d, 1H),5.33 (d, 1H), 6.00 (s, 1H), 6.44 (d, 1H), 6.65 (d, 1H), 7.12 (d, 1H),7.18 (d, 1H), 7.36 (d, 1H), 7.49 (t, 1H), 8.52 (s, 1H), 9.02 (s, 1H),12.46 (s, 1H)

Example 245(+)-5-{[6-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-amino}-phthalazin-1-one

Analogously to Example 3, 82 mg of the title compound is obtainedstarting from 100 mg of(+)-5-{[6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronapthalen-1-yl]amino}-phthalazin-1-onewith 2.1 ml of BBr₃ solution (1 M in dichloromethane) in 1 ml ofdichloromethane at 40° C.

¹H-NMR (DMSO): δ=1.43 (s, 1H), 1.56 (s, 3H), 1.91 (d, 1H), 2.01 (d, 1H),5.33 (d, 1H), 6.00 (s, 1H), 6.44 (d, 1H), 6.65 (d, 1H), 7.12 (d, 1H),7.18 (d, 1H), 7.36 (d, 1H), 7.49 (t, 1H), 8.52 (s, 1H), 9.02 (s, 1H),12.46 (s, 1H)

Example 2465-{[2-Hydroxy-5-methoxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-one

Analogously to Example 10, the corresponding imine is produced startingfrom 500 mg of4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 287 mg of 5-amino-phthalazin-1-one. As in Example 3, 320 mg of theimine is reacted by reaction with 7.2 ml of titanium tetrachloride (1 Min dichloromethane) in 20 ml of dichloromethane, and 80 mg of the titlecompound is obtained.

¹H-NMR (DMSO): δ=1.43 (s, 1H), 1.57 (s, 3H), 1.95 (d, 1H), 2.06 (d, 1H),2.15 (s, 3H), 3.80 (s, 3H), 5.38 (d, 1H), 5.99 (s, 1H), 6.53 (d, 1H),6.66 (s, 1H), 6.79 (s, 1H), 7.25 (d, 1H), 7.44 (d, 1H), 7.57 (t, 1H),8.61 (s, 1H), 12.54 (s, 1H)

Examples 247 and 248(−)-5-{[2-Hydroxy-5-methoxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-oneand(+)-5-{[2-Hydroxy-5-methoxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-oneSeparation of(+/−)-5-{[6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one

The enantiomer mixture is separated with ethanol as an eluant bychromatography on chiral carrier material (CHIRALPAK AD®, DAICELCompany). The

(−)-enantiomer: MS (EI): M⁺=447, [α]_(D)=3.4° °(c=0.7, CHCl₃) and the

(+)-enantiomer: MS (EI): M⁺=447, [α]_(D)=3.7° °(c=1.1, CHCl₃) are thusobtained.

Example 2495-{[2-Hydroxy-5-methoxy-2-(pentafluoroethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-one

Analogously to Example 10, the corresponding imine is produced startingfrom 250 mg of4-(2-methoxy-4-methyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanaland 118 mg of 5-amino-phthalazin-1-one. As in Example 3, 65 mg of theimine is reacted by reaction with 0.38 ml of titanium tetrachloride (1 Min dichloromethane) in 6 ml of dichloromethane, and 8 mg of the titlecompound is obtained.

¹H-NMR (CD₃OD): δ=1.40 (s, 1H), 1.55 (s, 3H), 2.19 (d, 1H), 2.29 (d,1H), 2.33 (s, 3H), 3.47 (s, 3H), 5.46 (s, 1H), 6.61 (s, 1H), 6.90 (s,1H), 7.54-7.63 (m, 2H), 7.63-7.73 (m, 2H), 8.43 (s, 1H)

Example 2505-{[6-Chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-8-fluoro-quinolin-2(1H)-one5-Amino-8-fluoroquinolin-2(1H)-one

10 g of 2,5-difluoroaniline and 6 g of pyridine in 350 ml ofdichloromethane are mixed drop by drop at 0° C. with 12.9 g of cinnamicacid chloride and stirred until conversion is completed at 0° C. Thebatch is added to 2N hydrochloric acid, and it is extracted withdichloromethane. It is washed with water, dried with sodium sulfate andconcentrated by evaporation in a vacuum. The solid that is obtained ismixed with 11.1 g of aluminum chloride and heated for 8 hours to 150° C.After chromatography on silica gel, 2.9 g of5,8-difluoroquinolin-2(1H)-one is obtained. The latter is reacted in 100ml of ethylene glycol in the presence of 780 mg of copper(II) oxide for20 hours at 200° C. in ammonia atmosphere at 60 bar. Afterchromatography on silica gel, in this case5-amino-8-fluoroquinolin-2(1H)-one is obtained as fraction A and2,5-diamino-8-fluoroquinoline is obtained as fraction B.

Fraction A: ¹H-NMR (DMSO): δ=5.73 (s, 2H), 6.28 (dd, 1H), 6.35 (d, 1H),7.07 (dd, 1H), 8.08 (dd, 1H), 11.31 (s, 1H).

Fraction B: ¹H-NMR (DMSO): δ=5.36 (s, 2H), 6.23 (dd, 1H), 6.47 (s, 2H),6.63 (d, 1H), 6.96 (dd, 1H), 8.07 (dd, 1H).

5-{[6-Chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-8-fluoro-quinolin-2(1H)-one

Analogously to Example 10, the corresponding imine is produced startingfrom 250 g of4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 137 mg of 5-amino-8-fluoroquinolin-2(1H)-one. The title compound isobtained analogously to Example 3 by reaction of the imine that isformed with 1.4 ml of titanium tetrachloride solution (1 M indichloromethane).

¹H-NMR (CD₃OD): δ=1.53 (s, 3H), 1.67 (s, 3H), 2.22 (s, 2H), 3.96 (s,3H), 5.14 (s, 1H), 6.51-6.61 (m, 2H), 7.09 (d, 1H), 7.20 (d, 1H), 7.24(dd, 1H), 8.21 (dd, 1H).

Example 2512-Amino-5-{[6-chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthlen-1-yl]amino}-8-fluoro-quinoline

Analogously to Example 10, the corresponding imine is produced startingfrom 250 g of4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanaland 137 mg of 2,5-diamino-8-fluoroquinoline. The title compound isobtained analogously to Example 3 by reaction of the imine that isformed with 1.0 ml of titanium tetrachloride solution (1 M indichloromethane).

¹H-NMR (CD₃OD): δ=1.54 (s, 3H), 1.67 (s, 3H), 2.20 (s, 2H), 3.94 (s,3H), 5.11 (s, 1 h), 6.43 (dd, 1H), 6.81 (d, 1H), 7.11 (d, 1H), 7.15 (d,1H), 7.20 (d, 1H), 8.18 (dd, 1H).

Examples 252 and 2535-{[4,4-Dimethyl-6-fluoro-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-8-fluoro-quinolin-2(1H)-oneand2-Amino-5-{[4,4-dimethyl-6-fluoro-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-8-fluoro-quinoline

Analogously to Example 10, a mixture of the corresponding imines isproduced starting from 237 g of4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 137 mg of a mixture that consists of5-amino-8-fluoroquinolin-2(1H)-one and 2,5-diamino-8-fluoroquinoline.Analogously to Example 3, the mixture of imines with 2.5 ml of titaniumtetrachloride solution (1 M in dichloromethane) is reacted, and the twotitle compounds are obtained after chromatography on silica gel.

Fraction A: ¹H-NMR (CD₃OD): δ=1.53 (s, 3H), 1.65 (s, 3H), 2.08 (d, 1H),2.23 (d, 1H), 3.95 (d, 3H), 5.11 (s, 1H), 6.50-6.61 (m, 2H), 6.98 (dd,1H), 7.06 (dd, 1H) 7.23 (dd, 1H), 8.22 (dd, 1H).

Fraction B: ¹H-NMR (CD₃OD): δ=1.52 (s, 3H), 1.66 (s, 3H), 2.08 (d, 1H),2.15 (d, 1H), 3.95 (d, 1H), 5.09 (s, 1H), 6.40-6.57 (m, 2H), 6.82 (d,1H), 6.94 (dd, 1H), 7.02-7.20 (m, 2H), 8.18 (t, 1H).

Example 2545-{[7-Fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclobutane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-one3-{([3-Fluoro-2-methoxyphenyl)-cyclobutyl}-2-hydroxy-2-(trifluoromethyl)-pentanal

Analogously to the synthesis of4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanalin Example 3,3-{(3-fluoro-2-methoxyphenyl)-cyclobutyl}-2-hydroxy-2-(trifluoromethyl)-pentanalis obtained starting from 2,6-difluoroanisole andcyclobutanecarbonitrile.

¹H-NMR (CDCl₃): δ=1.75-1.90 (m, 1H), 2.10-2.40 (m, 3H), 2.46-2.57 (m,2H), 2.83 (d, 1H), 3.00 (d, 1H), 3.94 (d, 3H), 6.75 (dt, 1H), 6.83-7.02(m, 2H), 8.94 (s, 1H).

5-{[7-Fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclobutane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-one

Analogously to Example 10, the corresponding imine is produced startingfrom 350 g of3-{(3-fluoro-2-methoxyphenyl)cyclobutyl}-2-hydroxy-2-(trifluoromethyl)pentanaland 200 mg of 5-amino-quinolin-2(1H)-one. Analogously to Example 3, theimine is reacted with 1.6 ml of titanium tetrachloride solution (1 M indichloromethane, and 35 mg of the title compound is obtained.

¹H-NMR (CD₃OD): δ=2.10-2.29 (m, 4H), 2.40-2.56 (m, 1H), 2.65-2.80 (m,2H), 2.93-3.06 (m, 1H), 4.09 (d, 3H), 5.14 (s, 1H), 6.49 (d, 1H), 6.63(d, 1H), 6.70 (d, 1H), 6.97 (d, 2H), 8.20 (d, 1H).

Example 2555-{[3,8-Dihydroxy-7-fluoro-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclobutane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-one

Analogously to Example 3, 12 mg of the title compound is obtainedstarting from 20 mg of5-{[7-fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclobutane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-onewith 0.22 ml of BBr₃ solution (1 M in dichloromethane) at roomtemperature.

¹H-NMR (CD₃OD): δ=1.81-1.94 (m, 1H), 2.08-2.27 (m, 3H), 2.28-2.41 (m,1H), 2.75 (d, 1H), 3.08 (q, 1H), 3.44 (q, 1H), 5.13 (s, 1H), 6.48 (d,1H), 6.63 (d, 1H), 6.68 (d, 1H), 6.73 (dd, 1H), 6.90 (dd, 1H), 7.37 (t,1H), 8.20 (d, 1H).

Example 2565-{[7-Fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopentane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-one3-{([3-Fluoro-2-methoxyphenyl)-cyclopentyl}-2-hydroxy-2-(trifluoromethyl)-pentanal

Analogously to the synthesis of4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanalin Example 3,3-{(3-fluoro-2-methoxyphenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethyl-pentanalstarting from 2,6-difluoroanisole and cyclopentanecarbonitrile isobtained.

¹H-NMR (CD₃OD): δ=1.15-2.26 (m, 8H), 2.33 (d, 1H), 3.11 (d, 1H), 3.57(s, 1H), 3.98 (d, 3H), 6.82-6.93 (m, 2H), 6.94-7.05 (m, 1H), 8.98 (s,1H).

5-{[7-Fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopentane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-one

Analogously to Example 10, the corresponding imine is produced startingfrom 350 g of3-{(3-fluoro-2-methoxyphenyl)cyclobutyl}-2-hydroxy-2-(trifluoromethyl)-pentanaland 190 mg of 5-amino-quinolin-2(1H)-one. Analogously to Example 3, theimine is reacted with 5.25 ml of titanium tetrachloride solution (1 M indichloromethane), and 193 mg of the title compound is obtained.

¹H-NMR (CDCl₃): δ=1.53-1.67 (m, 1H), 1.73-2.15 (m, 6H), 2.28-2.48 (m,3H), 3.95 (d, 3H), 4.81 (bs, 1H), 5.06 (d, 1H), 5.55 (d, 1H), 6.47-6.58(m, 3H), 6.82 (dd, 1H), 6.93 (dd, 1H), 7.32 (t, 1H), 8.18 (d, 1H).

Example 2575-{[3,8-Dihydroxy-7-fluoro-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopentane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-one

Analogously to Example 3, 17 mg of the title compound is obtainedstarting from 60 mg of5-{[7-fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopentane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-onewith 0.25 ml of BBr₃ solution (1 M in dichloromethane) at roomtemperature.

¹H-NMR (CD₃OD): δ=1.45-1.57 (m, 1H), 1.72-1.88 (m, 2H), 1.90-2.12 (m,3H), 2.18-2.43 (m, 3H), 2.70-2.85 (m, 1H), 5.18 (s, 1H), 6.51 (d, 1H),6.63 (d, 1H), 6.70 (d, 1H), 6.78 (dd, 1H), 6.87 (dd, 1H), 7.38 (t, 1H),8.22 (d, 1H).

Example 2585-{[2,5-Dihydroxy-4,4-dimethyl-7-fluoro-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one

Analogously to Example 10, the corresponding imine is produced startingfrom 1.0 g of4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 560 mg of 5-amino-2-methylphthalazin-1-one. As in Example 3, theimine that is formed is reacted by reaction with 10 ml of borontribromide solution (1 M in dichloromethane), and 45 mg of the titlecompound is obtained.

¹H-NMR (DMSO): δ=1.47 (s, 3H), 1.59 (s, 3H), 1.97 (d, 1H), 2.07 (d, 1H),3.70 (s, 3H), 5.41 (s, 1H), 6.11 (s, 1H), 6.41 (dd, 1H), 6.56 (dd, 1H),7.27 (d, 1H), 7.48 (d, 1H), 7.59 (t, 1H), 8.63 (s, 1H), 10.00 (s, 1H).

Examples 259 and 260(−)-5-{[2,5-Dihydroxy-4,4-dimethyl-7-fluoro-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-oneand(+)-5-{[2,5-Dihydroxy-4,4-dimethyl-7-fluoro-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-oneSeparation of(+/−)-5-{[2,5-dihydroxy-4,4-dimethyl-7-fluoro-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10,vvv). The

(−)-enantiomer: MS (EI): M⁺=451, [α]_(D)−34.6° °(c=1.3, CHCl₃) and the

(+)-enantiomer: MS (EI): M⁺=451, [α]_(D)+35.4° °(c=1.3, CHCl₃) are thusobtained.

Examples 261 and 2625-{(7-Bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one,Diastereomer B and5-{(7-Bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one,Diastereomer A

Analogously to Example 10, the corresponding imine is produced startingfrom 800 mg of4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 380 mg of 5-amino-2-methylphthalazin-1-one. As in Example 3, theimine that is formed is reacted by reaction with 9.4 ml of borontribromide solution (1 M in dichloromethane), and 37 mg of diastereomerB of5-{[7-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-oneis obtained as fraction A and 11 mg of diastereomer A of5-{[7-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-oneis obtained as fraction B.

Fraction A: ¹H-NMR (CD₃OD): δ=1.40 (s, 3H), 1.55 (s, 3H), 1.92 (d, 1H),2.25 (d, 1H), 3.84 (s, 3H), 5.27 (s, 1H), 6.70 (d, 1H), 7.19-7.29 (m,2H), 7.51 (t, 1H), 7.60 (d, 1H), 8.52 (s, 1H).

Fraction B: ¹H-NMR (CD₃OD): δ=1.55 (s, 3H), 1.66 (s, 3H), 2.07 (d, 1H),2.15 (d, 1H), 3.83 (s, 3H), 5.24 (s, 1H), 6.88 (d, 1H), 6.94 (d, 1H),7.18-7.28 (m, 1H), 7.62-7.70 (m, 2H), 8.56 (s, 1H).

Example 2635-{[7-Chloro-3,8-dihydroxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1′-naphthalen-4-yl)]amino}-quinolin-2(1H)-one3-[1-(3-Chloro-2-methoxyphenyl)-cyclohexyl]-2-hydroxy-2-(trifluoromethyl)propanal

9.57 g (30.79 mmol) of3-[1-(3-chloro-2-methoxyphenyl)-cyclohexyl]-2-oxopropionic acid (thiscompound was produced starting from the corresponding startingmaterials, analogously to the instructions described in WO 98/54159) ismixed with 191 ml of ethanol and 3.4 ml of concentrated sulfuric acid.After five hours of refluxing, the batch is spun in until a dry state isreached, and the residue is mixed with 500 ml of saturated sodiumbicarbonate solution. The aqueous phase is extracted three times withethyl acetate, and the combined organic extracts are washed with brine.After the solvent is dried and spun off, the residue is chromatographedon silica gel (mobile solvent ethyl acetate/hexane). 7.07 g (67.8%) ofthe desired ester is obtained.

7.07 g (20.87 mmol) ofethyl-3-[1-(3-chloro-2-methoxyphenyl)-cyclohexyl]-2-oxopropionate isdissolved in 33 ml of tetrahydrofuran and mixed with 3.56 g (25.04 mmol)of (trifluoromethyl)-trimethylsilane. After 51.1 mg oftetrabutylammonium fluoride is added, the batch is stirred overnight.The reaction mixture is diluted with methyl tert-butyl ether, washedonce with water and then with brine. After conventional working-up, theresidue is chromatographed on silica gel (mobile solvent ethylacetate/hexane). The isolated 5.71 g (60.4%) of the product is mixed in70 ml of tetrahydrofuran with 3.98 g (12.61 mmol) of tetrabutylammoniumfluoride and stirred for one hour at room temperature. After thereaction mixture is mixed with water, it is extracted with methyltert-butyl ether. After conventional working-up, the residue ischromatographed on a Flashmaster. 2.63 g (51.1%) of the desiredcompound:ethyl-2-[1-(3-chloro-2-methoxyphenyl)-cyclohexylmethyl]-3,3,3-trifluoro-2-hydroxypropionateis isolated.

1.59 g (3.89 mmol) of the above-described ester is dissolved in 14 ml ofdiethyl ether and mixed at 0° C. in portions with 110.7 mg (2.92 mmol)of lithium aluminum hydride. After two hours of stirring between 0 and5° C., 3.4 ml of saturated sodium bicarbonate solution is carefullyadded in drops. It is stirred vigorously for ten minutes at roomtemperature. After repeated extraction of the aqueous phase with methyltert-butyl ether, the combined organic extracts are treated as usual.After chromatography on a Flashmaster, 750 mg (52.8%) of a mixture isobtained, which consists of the desired aldehyde in two thirds andconsists of the ester in one third. In addition, 201.4 mg of thecorresponding alcohol (COntaminated) is obtained.

5-{2-[1-(3-Chloro-2-methoxyphenyl)-cyclohexylmethyl]-3,3,3-trifluoro-2-hydroxypropylidenamino}-1H-quinolin-2-one

375 mg (0.683 mmol) of the aldehyde that is described in the paragraphabove (together with the ester) is refluxed in 3.6 ml of xylene with109.4 mg (0.683 mmol) of 5-amino-1H-quinolin-2-one and 388.3 mg (1.366mmol) of titanium(IV) isopropylate for three hours. After cooling, thereaction mixture is mixed with saturated sodium chloride solution andethyl acetate. After ten minutes of vigorous stirring, the mixture isadded to Extrelut and eluted with 100 ml of dichloromethane. After thesolvent is spun off, the remaining residue is chromatographed on aFlashmaster. In addition to 145 mg of ester, 231.6 mg (66.9%, relativeto the content of aldehyde) of the desired imine is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.15-2.18 (9H), 2.38-2.65 (2H), 2.96 (1H),3.93 (3H), 4.61 (1H), 6.40-6.60 (2H), 6.62-6.81 (2H), 7.08 (1H),7.29-7.59 (3H), 8.07 (1H), 12.28 (1H).

5-{[7-Chloro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1′-naphthalen-4-yl)]amino}-quinolin-2(1H)-one

151.6 mg (0.299 mmol) of the above-described imine is dissolved in 2.8ml of dichloromethane. After the dropwise addition of 1.96 ml (1.796mmol) of titanium tetrachloride at −15° C., it is stirred for four hoursat this temperature. At 0° C., saturated sodium bicarbonate solution iscarefully added, and the reaction mixture is extracted three times withethyl acetate. The combined organic extracts are washed with brine,dried, and the solvent is spun off. After chromatography on aFlashmaster, 67.9 mg (44.8%) of the desired compound is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.30-1.90 (8H), 2.18 (1H), 2.30-2.50 (1H),2.53-2.70 (1H), 2.90 (1H), 4.00 (3H), 5.19 (1H), 6.52 (1H), 6.62 (1H),6.70 (1H), 7.09 (1H), 7.23 (1H), 7.38 (1H), 8.23 (1H).

5-{[7-Chloro-3,8-dihydroxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1′-naphthalen-4-yl)]amino}-quinolin-2(1H)-one

65.9 mg (0.13 mmol) of the cyclic ether that is described in the sectionabove is mixed with 2.6 m of boron tribromide (1 M in dichloromethane)and stirred for three hours at room temperature. At −5° C., saturatedsodium bicarbonate solution is carefully added in drops, and thereaction mixture is then extracted three times with ethyl acetate. Thecombined organic extracts are dried on sodium sulfate, and the residuethat remains after the solvent is spun off is chromatographed on aFlashmaster. 51.3 mg (80.1%) of the desired phenol is isolated.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.15-1.87 (8H), 2.01 (1H), 2.40-2.90 (3H,the DMSO signal is in this range), 5.29 (1H), 6.02 (1H), 6.20 (1H), 6.43(1H), 6.48-6.65 (2H), 6.75 (1H), 7.15-7.30 (2H), 8.20 (1H), 9.10 (1H),11.58 (1H).

Example 2645-{[7-Chloro-3,8-dihydroxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1′-naphthalen-4-yl)]amino}-2H-isoquinolin-1-one5-{[7-Chloro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1′-naphthalen-4-yl)]amino}-2H-isoquinolin-1-one

149.7 mg (0.295 mmol) of the imine (produced according to theinstructions described in Example 263 with use of the correspondingstarting materials) is cyclized with 1.93 ml (1.772 mmol) of titaniumtetrachloride. After conventional working-up and chromatography, 34.9 m(23.3%) of the desired compound is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.20-1.85 (8H), 2.05-2.50 (3H), 2.69 (1H),3.93 (3H), 5.34 (1H), 5.98 (1H), 6.13 (1H), 6.80 (1H), 6.97 (1H), 7.05(1H), 7.18 (1H), 7.20-7.38 (2H), 7.50 (1H), 11.25 (1H).

5-{[7-Chloro-3,8-dihydroxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1′-naphthalen-4-yl)]amino}-2H-isoquinolin-1-one

26.8 mg (0.053 mmol) of the above-described ether is subjected to ethercleavage as described in Example 263. After carrying out the reaction inthe usual way and after chromatography, 13.5 mg (51.8%) of the desiredphenol is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.15-1.85 (8H), 2.00 (1H), 2.40-2.90 (3H),5.30 (1H), 5.95 (1H), 6.09 (1H), 6.73 (1H), 6.81 (1H), 7.04 (1H),7.10-7.30 (3H), 7.50 (1H), 9.12 (1H), 11.23 (1H).

Example 2657′-Chloro-4′-[(8-fluoro-2-methylquinazolin-5-yl)amino]-3,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen]-3′-ol

1.61 ml (1.488 mmol) of titanium(IV) chloride is added in drops at −20°C. to 129.8 mg (0.248 mmol) of the corresponding imine, dissolved in 2.4ml of dichloromethane. After 1½ hours of stirring in a temperature rangeof between −20° C. and +5° C., the batch is worked up as usual. Afterchromatography on a Flashmaster,

11.4 mg (8.8%) of the desired compound is isolated.

MS (CI): 524 (100%)

Example 2665-{[7-Chloro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopropyl-1,1′-naphthalen-4-yl)]amino}-quinolin-2(1H)-one3-[1-(3-Chloro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)propanal

15.12 g (56.27 mmol) of3-[1-(3-chloro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionic acid (thiscompound was produced starting from the corresponding startingmaterials, analogously to the instructions described in WO 98/54159) ismixed with 350 ml of ethanol and 6.3 ml of concentrated sulfuric acid.After five hours of refluxing, the batch is spun in until a dry state isreached, and the residue is mixed with 700 ml of saturated sodiumbicarbonate solution. The aqueous phase is extracted three times withethyl acetate, and the combined organic extracts are washed with sodiumbicarbonate solution and brine. After the solvent is dried and spun off,the residue is chromatographed on silica gel (mobile solvent ethylacetate/hexane). 12.36 g (74%) of the desired ester is obtained.

6.18 g (20.83 mmol) ofethyl-3-[1-(3-chloro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionate isdissolved in 33 ml of tetrahydrofuran and mixed with 3.55 g (24.99 mmol)of (trifluoromethyl)-trimethylsilane. After 51 mg of tetrabutylammoniumfluoride is added, the batch is stirred overnight. The reaction mixtureis diluted with methyl tert-butyl ether, washed once with water and thenwith brine. After conventional working-up, the residue ischromatographed on silica gel (mobile solvent ethyl acetate/hexane). Theisolated 5.65 g (66.4%) of product is mixed in 76 ml of tetrahydrofuranwith 4.34 g (13.75 mmol) of tetrabutylammonium fluoride, and it isstirred for one hour at room temperature. After the reaction mixture ismixed with water, it is extracted with methyl tert-butyl ether. Afterconventional working-up, the residue is chromatographed on aFlashmaster. 2.39 g (47.4%) of the desired compound:ethyl-2-[1-(3-chloro-2-methoxyphenyl)-cyclopropylmethyl]-3,3,3-trifluoro-2-hydroxypropionateis isolated.

0.850 mg (2.32 mmol) of the above-described ester is dissolved in 8 mlof diethyl ether and mixed at 0° C. in portions with 66 mg (1.74 mmol)of lithium aluminum hydride. After two hours of stirring between 0 and5° C., 2.7 ml of saturated sodium bicarbonate solution is carefullyadded in drops. It is stirred vigorously at room temperature for 10minutes. After repeated extraction of the aqueous phase with methyltert-butyl ether, the combined organic extracts are treated as usual.After chromatography on a Flashmaster, 490 mg (65.5%) of a mixture isobtained, which consists of just under two thirds of the desiredaldehyde and one third of the ester.

5-{2-[1-(3-Chloro-2-methoxyphenyl)-cyclopropylmethyl]-3,3,3-trifluoro-2-hydroxy-propylidenamino}-1H-quinolin-2-one

490 mg (0.972 mmol) of the aldehyde that is described in the sectionabove (as a mixture with the ester) is refluxed in 5.1 ml of xylene with155.7 mg (0.972 mmol) of 5-amino-1H-quinolin-2-one and 552.6 mg (1.944mmol) of titanium(IV) isopropylate for three hours. After cooling, thereaction mixture is mixed with saturated sodium chloride solution andethyl acetate. After ten minutes of vigorous stirring, the mixture isadded to Extrelut and eluted with 200 ml of dichloromethane. After thesolvent is spun off, the remaining residue is chromatographed on aFlashmaster. In addition to 93.9 mg of ester, 312.8 mg (69.2%, relativeto the aldehyde content), of the desired imine is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=0.63-0.75 (1H), 0.79-0.90 (1H), 1.04-1.19(2H), 2.10 (1H), 3.10 (1H), 4.00 (3H), 4.73 (1H), 6.74 (1H), 6.64 (1H),6.75 (1H), 6.88-7.02 (2H), 7.29-7.43 (2H), 7.70 (1H), 8.10 (1H), 12.32(1H).

5-{[7-Chloro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopropane-1,1′-naphthalen-4-yl)]amino}-quinolin-2(1H)-one

232.8 mg (0.501 mmol) of the above-described imine is dissolved in 4.7ml of dichloromethane. After dropwise addition of 3.3 ml (3.009 mmol) oftitanium tetrachloride at −20° C., it is stirred for four hours at thistemperature. At 0° C., saturated sodium bicarbonate solution iscarefully added, and the reaction mixture is extracted three times withethyl acetate. The combined organic extracts are washed with brine,dried, and the solvent is spun off. After chromatography on aFlashmaster, 111.8 mg (48%) of the desired compound is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=0.78-1.15 (3H), 1.78-2.09 (3H), 3.75 (3H),5.06 (1H), 6.10-6.30 (3H), 6.45 (1H), 6.60 (1H), 6.98 (1H), 7.20 (1H),7.30 (1H), 8.23 (1H), 11.60 (1H).

Example 2675-{[7-Chloro-3,8-dihydroxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopropane-1,1′-naphthalen-4-yl)]amino}-2H-isoquinolin-1-one5-{[7-Chloro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopropane-1,1′-naphthalen-4-yl)]amino}-2H-isoquinolin-1-one

113.8 mg (0.245 mmol) of the imine (produced according to theinstructions, described in Example 263, with use of the correspondingstarting materials), dissolved in 2.3 ml of dichloromethane, is cyclizedwith 1.6 ml (1.472 mmol) of titanium tetrachloride. After conventionalworking-up and chromatography, 36.8 m (32.3%) of the desired compound isobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ=0.80-1.12 (3H), 1.82-2.09 (3H), 3.76 (3H),5.09 (1H), 5.95 (1H), 6.37 (1H), 6.68 (1H), 6.81 (1H), 6.96 (1H),7.16-7.28 (2H), 7.30 (1H), 7.52 (1H), 11.30 (1H).

5-{[7-Chloro-3,8-dihydroxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cycloptopan-1,1′-naphthalen-4-yl)]amino}-2H-isoquinolin-1-one

22.7 mg (0.049 mmol) of the above-described ether is subject to ethercleavage as described in Example 263. After carrying out the reaction inthe usual way and after chromatography, 10.9 mg (45.5%) of the desiredphenol is obtained.

¹H-NMR (400 MHz, CD₃OD): δ=0.55-0.63 (1H), 0.73-0.84 (1H), 1.40-1.51(1H), 1.80 (1H), 1.95-2.10 (2H), 5.02 (1H), 6.69 (1H), 6.75 (1H), 6.80(1H), 6.98 (1H), 7.08 (1H), 7.25 (1H), 7.59 (1H).

Example 2687′-Chloro-4′-[(8-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)spiro[cyclopropane-1,1°(2′H)-naphthalene]-3′,8′-diol7′-Chloro-4′-[(8-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalen]-3′-ol

1.64 ml (1.512 mmol) of titanium(IV) chloride is added in drops at −20°C. to 121.3 mg (0.252 mmol) of the corresponding imine, dissolved in 2.4ml of dichloromethane. After 1½ hours of stirring in a temperature rangeof between −20° C. and +5° C., the batch is worked up as usual. Afterchromatography on a Flashmaster, 7.4 mg (6.1%) of the desired compound(slightly contaminated) is isolated.

¹H-NMR (400 MHz, CDCl₃): δ=0.84-1.10 (3H), 1.92-2.13 (3H), 2.82 (3H),3.79 (3H), 4.90 (1H), 5.65 (1H), 6.34 (1H), 7.00 (1H), 7.16 (1H), 7.37(1H), 9.35 (1H).

7′-Chloro-4′-[(8-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)spiro[cyclopropane-1,1′(2′H)-naphthalene]-3′,8′-diol

40 mg (0.083 mmol) of the corresponding imine is mixed at 0° C. with 1.1ml of a 1 M solution of boron tribromide in dichloromethane. After ¾hour of stirring at this temperature, saturated sodium bicarbonatesolution is carefully added in drops, and the reaction mixture is thenextracted three times with ethyl acetate. The combined organic extractsare washed with brine, dried, and the solvent is spun off. Afterchromatography on a Flashmaster, 15 mg (38.6%) of the desired phenol isobtained.

MS (CI): 468 (100%)

Example 269[6-Hydroxy-1-methoxy-8,8-dimethyl-5-(2-oxo-1,2-dihydroquinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-acetonitrileMethyl-2-methoxy-3-methylbenzoate (RS 2690 F2)

199.9 g (1.45 mol) of potassium carbonate is introduced into 1.5 1 ofdimethylformamide. At room temperature, 100 g (657.29 mol) of2-hydroxy-3-methylbenzoic acid, dissolved in 250 ml ofdimethylformamide, is added in drops. After 30 minutes of stirring, 90ml of methyl iodide is added in drops, and the batch is stirredovernight. The reaction mixture is added to ice water and extractedthree times with methyl tert-butyl ether. The organic phases are washedwith water and brine. After drying, the solvent is spun off, and theresidue is chromatographed on silica gel (mobile solvent ethylacetate/hexane). 70.21 g (59.3%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=2.32 (3H), 3.85 (3H), 3.93 (3H), 7.07 (1H),7.35 (1H), 7.65 (1H).

2-(2-Methoxy-3-methylphenyl)-propan-2-ol

70.21 g (389.64 mmol) of methyl-2-methoxy-3-methylbenzoate, dissolved in640 ml of tetrahydrofuran, is added in drops to 311.7 ml ofmethylmagnesium bromide in diethyl ether (3M). In this case, thereaction mixture is heated to about 48° C. The batch is stirred forthree hours at room temperature. About 1.5 l of saturated ammoniumchloride solution is now added in drops while being cooled in an icebath, and it is stirred vigorously for one hour. After 3× extractionwith methyl tert-butyl ether, the combined organic extracts are washedwith brine, dried, and the solvent is spun off. 71.37 g (>100%) of thedesired compound, which is further incorporated in crude form, isisolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.65 (6H), 2.33 (3H), 3.89 (3H), 4.55 (1H),6.99 (1H), 7.10 (1H), 7.18 (1H).

Ethyl-4-(2-methoxy-3-methylphenyl)-4-methyl-2-oxopentanoate

71.37 g (395.96 mmol) of 2-(2-methoxy-3-methylphenyl)-propan-2-ol and149 g (791.92 mmol) of 2-trimethylsilanyloxyacrylic acid ethyl ester areintroduced into 1.1 l of dichloromethane. At −78° C., 44.8 ml (379.91mmol) of tin tetrachloride is added in drops, and the batch is thenstirred for three hours at this low temperature. 1.4 1 ofsemiconcentrated potassium carbonate solution is carefully added indrops, and the reaction mixture is thus brought to room temperature. Thebatch is filtered, and the filtrate is extracted three times with ethylacetate. The combined organic extracts are washed with brine, dried onsodium sulfate, and the solvent is spun off. The residue ischromatographed several times on silica gel (mobile solvent ethylacetate/hexane). 45.81 g (41.6%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.30 (3H), 1.50 (6H), 2.30 (3H), 3.39 (2H),3.78 (3H), 4.17 (2H), 6.97 (1H), 7.07 (1H), 7.15 (1H).

Ethyl-2-hydroxy-4-(2-methoxy-3-methylphenyl)-4-methyl-2-(trifluoromethyl)pentanoate

20 g (71.90) ofethyl-4-(2-methoxy-3-methylphenyl)-4-methyl-2-oxopentanoate and 12.3 g(86.28 mmol) of trifluoromethyl)trimethylsilane are introduced into 117ml of tetrahydrofuran. At room temperature, 180 mg of tetrabutylammoniumfluoride is added (heating to about 35° C.). After stirring overnight,22.7 g (71.90 mmol) of tetrabutylammonium fluoride is added, and thebatch is stirred for three hours at room temperature. After dilutionwith methyl tert-butyl ether, the organic phase is washed three timeswith water and once with brine. After the solvent is dried and spun off,the residue is chromatographed on silica gel (mobile solvent ethylacetate/hexane). 16.33 g (65.2%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.19 (3H), 1.43 (3H), 1.49 (3H), 2.30-2.44(4H), 2.82 (1H), 3.50-3.68 (2H), 3.84 (3H), 4.00-4.13 (2H), 6.92 (1H),7.00-7.10 (2H).

4-(2-Methoxy-3-methylphenyl)-4-methyl-(trifluoromethyl)-pentane-1,2-diol

16.33 g (46.88 mmol) of the above-described ester is dissolved in 160 mlof diethyl ether and mixed at 0° C. in portions with 3.56 g (93.76 mmol)of lithium aluminum hydride. After stirring over a weekend at roomtemperature, saturated sodium bicarbonate solution is carefully added indrops and then stirred vigorously for one hour. After 3× extraction withmethyl tert-butyl ether, the combined organic extracts are washed withbrine, dried, and the residue is chromatographed on silica gel after thesolvent is spun off (mobile solvent ethyl acetate/hexane). 10.76 g(74.9%) of the desired diol is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.49 (3H), 1.58 (3H), 1.84 (1H), 2.24 (1H),2.36 (3H), 2.59 (1H), 2.88 (1H), 3.28-3.40 (2H), 3.88 (3H), 6.99 (1H),7.10 (1H), 7.20 (2H).

4-(3-Bromomethyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol

3 g (9.79 mmol) of4-(2-methoxy-3-methylphenyl)-4-methyl-(trifluoromethyl)-pentane-1,2-diolis dissolved in 22 ml of carbon tetrachloride, mixed with 1.91 g (10.60mmol) of NBS and 5 mg of benzoyl peroxide and refluxed for 24 hours.After the succinimide is filtered off through a glass-fiber filter, itis rewashed with dichloromethane, and the solvent is spun off. Theresidue (5.42 g>100%) is incorporated in crude form into the next stage.

[2-Methoxy-3-(4,4,4-trifluoro-3-hydroxy-3-hydroxymethyl-1,1-dimethylbutyl)phenyl]acetonitrile

5.42 g (14.07 mmol) of the above-described bromine compound is mixed ina mixture that consists of dimethylformamide and water (14 and 10.5 ml)with 1.37 g (14.07 mmol) of potassium cyanide and stirred overnight atroom temperature. The reaction mixture is mixed with water and extractedthree times with methyl tert-butyl ether. The combined organic phasesare washed with brine, and the solvent is spun off after drying. 2.6 g(55.8%) of the desired compound is obtained after chromatography on aFlashmaster.

¹H-NMR (300 MHz, CDCl₃): δ=1.49 (3H), 1.60 (3H), 1.72 (1H), 2.22 (1H),2.50 (1H), 2.92 (1H), 3.20-3.45 (2H), 3.80 (2H), 3.88 (3H), 7.13 (1H),7.30-7.42 (2H).

[2-Methoxy-3-(4,4,4-trifluoro-3-hydroxy-3-formyl-1,1-dimethylbutyl)phenyl]acetonitrile

0.26 ml (2.99 mmol) of oxalyl chloride is cooled in 6.6 ml ofdichloromethane to −78° C. After dropwise addition of 0.42 ml (5.98mmol) of dimethyl sulfoxide, dissolved in 1.2 ml of dichloromethane, itis stirred for 10 more minutes and then 900 mg (2.72 mmol) of[2-methoxy-3-(4,4,4-trifluoro-3-hydroxy-3-hydroxymethyl-1,1-dimethylbutyl)phenyl]acetonitrilein 2.6 ml of dichloromethane is added in drops. After two hours ofstirring at −78° C., 1.88 ml (13.58 mmol) of triethylamine is added indrops, the batch is allowed to come to room temperature, and then it isstirred for 1½ hours at room temperature. After mixing with water, it isextracted three times with dichloromethane. The combined organicextracts are washed with 1% sulfuric acid, with saturated sodiumbicarbonate solution and with brine. After the solvent is dried and spunoff, the residue is chromatographed on a Flashmaster. 599.4 mg (67.1%)of the desired aldehyde remains.

¹H-NMR (300 MHz, CDCl₃): δ=1.45 (3H), 1.51 (3H), 2.32 (1H), 3.20 (1H),3.51 (1H), 3.78 (2H), 3.89 (3H), 7.09 (1H), 7.19 (1H), 7.35 (1H), 9.06(1H).

{2-Methoxy-3-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-[(2-oxo-1,2-dihydroquinolin-5-ylimino)-methyl]-butyl)-phenyl}acetonitrile

200 mg (0.607 mmol) of the above-described aldehyde in 3.4 ml of xyleneis refluxed for three hours with 97.3 mg (0.607 mmol) of5-amino-1H-quinolin-2-one and 345.1 mg (1.214 mmol) of titanium(IV)isopropylate for three hours. After the reaction is completed, brinesolution and ethyl acetate are added. After 30 minutes of vigorousstirring at room temperature, the batch is added to Extrelut and elutedwith 200 ml of dichloromethane. After the solvent is spun off, theresidue is chromatographed on a Flashmaster. 228.7 mg (79.8%) of thedesired imine is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.45 (3H), 1.59 (3H), 2.38 (1H), 3.26 (1H),3.34-3.55 (2H), 3.85 (3H), 4.66 (1H), 6.29 (1H), 6.69-6.80 (2H), 6.90(1H), 7.16 (1H), 7.30-7.47 (2H), 7.51 (1H), 7.97 (1H), 12.18 (1H).

6-Hydroxy-1-methoxy-8,8-dimethyl-5-(2-oxo-1,2-dihydroquinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-acetonitrile

141.2 mg (0.299 mmol) of imine is mixed at 0° C. with 4.5 ml of a 1 Msolution of boron tribromide in dichloromethane, and it is stirred forfour hours. After the dropwise addition of saturated sodium bicarbonatesolution, it is extracted three times with ethyl acetate. The combinedorganic extracts are washed with brine. After the solvent is dried andspun off, the residue is chromatographed on a Flashmaster. 8 mg (5.8%)of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.52 (3H), 1.70 (3H), 2.05 (1H), 2.19 (1H),3.69 (2H), 3.79 (3H), 5.00-5.16 (2H), 5.64 (1H), 6.38 (1H), 6.50 (1H),6.62 (1H), 7.05-7.19 (2H), 7.30 (1H), 8.15 (1H), 10.76 (1H).

Example 270[5-(8-Fluoro-2-methylquinazolin-5-ylamino)-6-hydroxy-1-methoxy-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-acetonitrile{2-Methoxy-3-[4,4,4-trifluoro-3-(8-fluoro-2-methylquinazolin-5yl-iminomethyl)-3-hydroxy-1,1-dimethylbutyl]phenyl}acetonitrile

200 mg (0.61 mmol) of the aldehyde that is described in Example 269 isrefluxed with 107.5 mg (0.61 mmol) of5-amino-8-fluoro-2-methylquinazoline and 345.1 mg (1.214 mmol) oftitanium tetrachloride in 3.4 ml of xylene for 3 hours. Afterconventional working-up and chromatography, 129.5 mg (43.7%) of thedesired imine is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.41 (3H), 1.67 (3H), 2.35 (1H), 2.99 (3H),3.35 (1H), 3.38-3.56 (2H), 3.85 (3H), 4.16 (1H), 6.50-6.60 (2H), 6.75(1H), 7.17 (1H), 7.45 (1H), 7.55 (1H), 9.47 (1H).

[5-(8-Fluoro-2-methylquinazolin-5-ylamino)-6-hydroxy-1-methoxy-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-acetonitrile

100.9 mg (0.21 mmol) of the above-described imine is cyclized and workedup as usual with 3.1 ml of a 1 M solution of boron tribromide indichloromethane at 0° C. After chromatography on a Flashmaster andsubsequent plate separation, 7.5 mg (7.7%) of the desired compound isisolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.58 (3H), 1.74 (3H), 2.09-2.28 (2H), 2.95(3H), 3.78 (2H), 3.83 (3H), 5.02 (1H), 5.30 (1H), 5.61 (1H), 6.69 (1H),7.18-7.32 (2H), 7.50 (1H), 9.38 (1H).

Example 2711-(7-Fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,6-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol2-Hydroxy-4-(2-methoxy-3-methylphenyl)-4-methyl-2-(trifluoromethyl)pentanal

2 g (6.53 mmol) of the4-(2-methoxy-3-methylphenyl)-4-methyl-(trifluoromethyl)-pentane-1,2-diolthat is described in Example 269 is oxidized to aldehyde according toSwern analogously to the description in this example. After conventionalworking-up and purification on a Flashmaster, 1.20 g (60.3%) of thedesired aldehyde is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.46 (3H), 1.50 (3H), 2.23 (1H), 2.32 (3H),3.38 (1H), 3.60 (1H), 3.85 (3H), 6.93 (1H), 7.00 (1H), 7.10 (1H), 8.95(1H).

1,1,1-Trifluoro-2-[(7-fluoro-2-methylquinazolin-5-ylimino)-methyl]-4-(2-methoxy-3-methylphenyl)-4-methylpentan-2-ol

150 mg (0.493 mmol) of the described aldehyde is reacted as usual and asalready described several times with 87.3 mg (0.498 mmol) of5-amino-7-fluoro-2-methylquinazoline and 280.3 mg (0.986 mmol) oftitanium tetraisopropylate in 2.5 ml of xylene to form imine. Afterchromatography, 174.9 mg (76.6%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.41 (3H), 1.65 (3H), 2.01 (3H), 2.29 (1H),2.90 (3H), 3.49 (1H), 3.80 (3H), 4.55 (1H), 6.19 (1H), 6.50-6.60 (2H),7.03 (1H), 7.40 (1H), 7.62 (1H), 9.30 (1H).

1-(7-Fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,6-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

174.9 mg (0.377 mmol) of the above-described imine is cyclized at 0° C.with titanium tetrachloride in dichloromethane. The execution,working-up and chromatography are carried out as already describedseveral times. 159.7 mg (91.3%) of the desired compound is isolated as adiastereomer mixture at a 9:1 ratio (the NMR data relative to the maindiastereomer).

¹H-NMR (300 MHz, CDCl₃): δ=1.59 (3H), 1.73 (3H), 2.10-2.28 (2H), 2.32(3H), 2.86 (3H), 3.81 (3H), 4.99 (1H), 6.05 (1H), 6.10 (broad, 1H), 6.52(1H), 6.89 (1H), 6.95-7.16 (2H), 9.20 (1H).

Example 2721-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,6-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol1,1,1-Trifluoro-2-[(7,8-difluoro-2-methylquinazolin-5-ylimino)-methyl]-4-(2-methoxy-3-methylphenyl)-4-methylpentan-2-ol

150 mg (0.493 mmol) of the described aldehyde is reacted as usual and asalready described several times with 96.2 mg (0.493 mmol) of5-amino-7,8-difluoro-2-methylquinazoline and 280.3 mg (0.986 mmol) oftitanium tetraisopropylate in 2.5 ml of xylene to form imine. Afterchromatography, 155.5 mg (65.5%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (3H), 1.63 (3H), 2.07 (3H), 2.28 (1H),2.98 (3H), 3.50 (1H), 3.83 (3H), 4.49 (1H), 6.28 (1H), 6.52-6.62 (2H),7.03 (1H), 7.62 (1H), 9.36 (1H).

1-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,6-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

155.5 mg (0.323 mmol) of the above-described imine is cyclized withtitanium tetrachloride in dichloromethane at 0° C. The execution,working-up and chromatography are carried out as already describedseveral times. 101.6 mg (65.3%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.60 (3H), 1.73 (3H), 2.08-2.28 (2H), 2.32(3H), 2.93 (3H), 3.81 (3H), 4.93 (1H), 5.42 (1H), 5.81 (1H), 6.58 (1H),6.95-7.09 (2H), 9.24 (1H).

Example 2735-[2,6-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-2-methyl-2H-phthalazin-1-one2-(3-Methoxyphenyl)-2-methylpropanenitrile

50 g (339.72 mmol) of 3-methoxybenzylcyanide is dissolved in 530 ml ofDMF and mixed with 96.4 g (6792.4 mmol) of methyl iodide. After coolingto 0° C., 21.5 g (492.2 mmol) of NaH (55% suspension) is added inportions to the reaction mixture within four hours. After 18 hours atroom temperature, the batch is poured into 700 ml of ice water andextracted three times with 500 ml each of diethyl ether. The combinedorganic phases are washed with water and brine. After drying on sodiumsulfate, the desiccant is filtered off, and the solvent is spun off in arotary evaporator. After chromatography on silica gel (mobile solventethyl acetate/hexane), 48.9 g (82.2%) of the desired compound isobtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.73 (6H), 3.85 (3H), 6.85 (1H), 7.02 (1H),7.07 (1H), 7.31 (1H).

2-(3-Methoxyphenyl)-2-methylpropanal

25 g (142.67 mmol) of the above-described nitrile is dissolved in 570 mlof toluene. At −65 to −60° C., 178 ml of a 1.2 molar solution of DIBAHin toluene is added in drops within 75 minutes. After two hours ofstirring at this temperature, 815 ml of a 20% L-(+)-tartaric acidsolution is begun to be added in drops. After 150 milliliters, thetemperature is increased to −10° C. The remainder of the tartaric acidsolution is quickly added, and the batch is stirred vigorously for 16hours at room temperature. The reaction mixture is shaken twice with 600ml each of diethyl ether. The combined organic extracts are shaken withwater and brine, dried, and the solvent is spun off. The residue that isobtained (25.1 g=98.8%) is incorporated in crude form into the nextstage.

¹H-NMR (300 MHz, CDCl₃): δ=1.47 (6H), 3.83 (3H), 6.78-6.90 (3H), 7.30(1H), 9.50 (1H).

Ethyl-E-4-(3-methoxyphenyl)-4-methylpent-2-enoate

33.6 g (114.3 mmol) of phosphonoacetic acid triethyl ester is introducedinto 148 ml of tetrahydrofuran. At 0° C., 79.7 ml of a 2 M solution ofLDA in THF/heptane/ethylbenzene is added in drops (1½ hours). After onehour of stirring, 24.3 g (136.34 mmol) of2-(3-methoxyphenyl)-2-methylpropanal, dissolved in 130 ml oftetrahydrofuran, is added in drops at 0° C. After five days of stirringat room temperature, the reaction mixture is poured into 250 ml ofdilute ammonium chloride solution and extracted twice with 400 ml eachof diethyl ether. The combined organic extracts are treated as usual,and the residue that is obtained is chromatographed on silica gel(mobile solvent ethyl acetate/hexane). 27.2 g (80.4%) of the desiredcompound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.30 (3H), 1.49 (6H), 3.81 (3H), 4.20 (2H),5.80 (1H), 6.78 (1H), 6.85 (1H), 6.90 (1H), 7.12 (1H), 7.25 (1H).

Ethyl-4-(3-methoxyphenyl)-4-methylpentanoate

27.2 g (109.5 mmol) of ethyl-E-4-(3-methoxyphenyl)-4-methylpent-2-enoateis mixed in 293 ml of ethyl acetate with 2.72 g of palladium on carbon(10%) and stirred under hydrogen atmosphere for 18 hours at roomtemperature. The catalyst is removed by filtration through a glass-fiberfilter, and the residue that remains after the concentration byevaporation (27.2 g=99.2%) is incorporated in crude form into the nextstage.

¹H-NMR (300 MHz, CDCl₃): δ=1.21 (3H), 1.32 (6H), 1.90-2.10 (4H), 3.82(3H), 4.05 (2H), 6.74 (1H), 6.89 (1H), 6.93 (1H), 7.25 (1H).

Ethyl-4-(3-methoxyphenyl)-2-hydroxy-4-methylpentanoate

27.2 g (108.65 mmol) of ethyl-4-(3-methoxyphenyl)-4-methylpentanoate isdissolved in 380 ml of tetrahydrofuran, and the reaction mixture iscooled to −70° C. to

-   -   −65° C. Within two hours, 304 ml of a 0.5 molar solution of        potassium-bis-(trimethylsilylamide) in toluene is added in        drops, and the reaction mixture is then stirred for 75 more        minutes at −70° C. 39.7 g (152.11 mmol) of Davis reagent,        dissolved in 380 ml of tetrahydrofuran, is now added in drops        within 90 minutes. After two hours of stirring at −70° C., 195        ml of saturated ammonium chloride solution is slowly added in        drops, the cold bath is removed and it is stirred vigorously for        thirty minutes. After extraction with diethyl ether (twice with        800 ml each), the combined organic extracts are treated as usual        with water and brine. After the solvent is spun off, the residue        is chromatographed on silica gel (mobile solvent ethyl        acetate/hexane). 20.9 g (72.4%) of the desired compound is        isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.29 (3H), 1.40 (3H), 1.48 (3H), 1.85 (1H),2.20 (1H), 2.50 (1H), 3.81 (3H), 3.99 (1H), 4.18 (2H), 6.76 (1H), 6.95(1H), 7.00 (1H), 7.28 (1H).

Ethyl-4-(3-methoxyphenyl)-4-methyl-2-oxopentanoate

2019 g (78.47 mmol) of ethyl4-(3-methoxyphenyl)-2-hydroxy-4-methyl-pentanoate is dissolved in 820 mlof dichloromethane and mixed with 273 ml of dimethyl sulfoxide. After39.7 g (392.36 mmol) of triethylamine is added, the batch is mixed inportions with 31.2 g (196.18 mmol) of SO₃/pyridine complex and thenstirred for 16 hours at room temperature. About 400 ml ofdichloromethane is drawn off in a rotary evaporator. Then, the reactionmixture is mixed with 312 ml of saturated ammonium chloride solutionwhile being cooled slightly, and it is stirred vigorously for 20minutes. After 2× extraction with diethyl ether (800 ml each), thecombined organic phases are washed with water and brine. The residuethat remains after the solvent is spun off is chromatographed on silicagel (mobile solvent ethyl acetate/hexane). 15.59 g (75.3%) of thedesired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.28 (3H), 1.48 (6H), 3.18 (2H), 3.80 (3H),4.12 (2H), 6.74 (1H), 6.90 (1H), 6.95 (1H), 7.25 (1H).

Ethyl-4-(3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoate

15.59 g (58.98 mmol) ofethyl-4-(3-methoxyphenyl)-4-methyl-2-oxopentanoate is dissolved in 96 mlof tetrahydrofuran and mixed at 0° C. with 10.1 g (70.78 mmol) of(trifluoromethyl)-trimethylsilane. After 144.5 mg of tetrabutylammoniumfluoride is added, it is stirred for 2¾ hours at 0 to 5° C. The batch isadded to 150 ml of ice water, extracted twice with diethyl ether (300 mleach), and the combined organic extracts are treated as usual. After thesolvent is spun off, the residue is chromatographed on silica gel(mobile solvent ethyl acetate/hexane). 17.10 g (71.3%) of the desiredproduct (COntaminated) is isolated, which is incorporated in crude forminto the next stage.

4-(3-Methoxyphenyl)-2-(trifluoromethyl)-pentane-1,2-diol

6.77 g (16.65 mmol) of (rac.)ethyl-4-(3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoateis dissolved in 61 ml of diethyl ether and mixed at 0° C. in portionswith 1.26 g (33.31 mmol) of lithium aluminum hydride. The reactionmixture is stirred for one hour at 5° C. and for 1½ hours at roomtemperature. For hydrolysis, the mixture is mixed drop by drop with 30ml of saturated NaHCO₃ solution while being cooled in an ice bath. It isvigorously stirred for one hour while being cooled in an ice bath andovernight at room temperature. The precipitate is suctioned off andwashed with diethyl ether. The filtrate is concentrated by evaporationin a rotary evaporator, and the residue is chromatographed on silica gel(mobile solvent ethyl acetate/hexane). 5.64 g (71.2%) of a mixture inwhich the trimethylsilyl group sits in part on the primary hydroxylgroup and in part on the secondary hydroxyl group is isolated. Themixture (5.64 g) is therefore dissolved in 72 ml of tetrahydrofuranwithout further purification and mixed with 4 g (12.79 mmol) oftetrabutylammonium fluoride trihydrate, and it is stirred for 90 minutesat room temperature. The reaction mixture is diluted with water andextracted twice with 150 ml each of diethyl ether. After the combinedorganic phases are washed with water and brine, the solvent is dried andspun off. The crude product (5.8 g) is chromatographed together withanother produced batch (7.97 g of feedstock; 10.4 g of yield of crudeproduct) on silica gel (mobile solvent ethyl acetate/hexane). 10.07 g ofthe desired diol is isolated from the two batches.

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (3H), 1.53 (3H), 2.10-2.25 (1H), 2.80(1H), 3.29-3.48 (2H), 3.83 (3H), 6.78 (1H), 6.97 (1H), 7.00 (1H), 7.28(1H).

4-(3-Methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal

10.07 g (34.45 mmol) of the above-described diol is oxidized to thecorresponding aldehyde as already described several times according toSwern. After chromatography on silica gel (mobile solvent ethylacetate/hexane), 7.16 g (71.6%) of the desired compound is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.38 (3H), 1.48 (3H), 2.32 (1H), 2.69 (1H),3.69 (1H), 3.82 (3H), 6.78 (1H), 6.88 (1H), 6.93 (1H), 7.25 (1H), 8.88(1H).

5-[4-(3-Methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidenamino)-2-methyl-2H-phthalazin-1-one

300 mg (1.033 mmol) of the above-described4-(3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal is reactedwith 180.9 mg (1.033 mmol) of 5-amino-2-methyl-2H-phthalazin-1-one toform imine. After reaction, conventional working-up and chromatography,318.2 mg (68.8%) of the desired imine is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.36 (3H), 1.55 (3H), 2.49 (1H), 2.78 (1H),3.50 (3H), 3.90 (3H), 4.72 (1H), 6.40 (1H), 6.59 (1H), 6.78 (1H), 6.90(1H), 7.05 (1H), 7.28 (1H), virtually under the chloroform), 7.53 (1H),8.30 (1H), 8.43 (1H).

5-(2-Hydroxy-6-methyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2-methyl-2H-phthalazin-1-one

100 mg (0.223 mmol) of imine is cyclized with titanium tetrachloride indichloromethane as described in Example 146. 43.4 mg (43.4%) of thedesired compound, specifically as a diastereomer mixture, is isolated.

MS (ES+): 448 (100%)

5-[2,6-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-]-ylamino]-2-methyl-2H-phthalazin-1-one

37 mg (0.082 mmol) of the ether that is described in the section aboveis reacted with boron tribromide as described in Example 146. After thereaction is carried out and after conventional working-up, 20.9 mg(58.4%) of the desired compound is obtained, specifically as adiastereomer mixture.

MS (ES+): 434 (100%)

Example 2741-(8-Fluoro-2-methylquinazolin-5-ylamino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol4-(3-Methoxyphenyl)-1,1,1-trifluoro-2-[([8-fluoro-2-methylquinazolin-5-ylimino]-methyl]-4-methyl-pentan-2-ol

400 mg (1.722 mmol) of4-(3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal is reacted asdescribed in Example 146 with 305.1 mg (1.722 mmol) of5-amino-8-fluoro-2-methylquinazoline to form imine. Afterchromatography, 494.4 mg (79.8%) of the desired imine is isolated.

¹H-NMR (CDCl₃): δ=1.34 (3H), 1.58 (3H), 2.40 (1H), 2.79 (1H), 3.00 (3H),3.48 (3H), 4.78 (1H), 6.29-6.42 (2H), 6.74 (1H), 6.90 (1H), 7.00 (1H),7.28-7.40 (2H), 9.64 (1H).

1-(8-Fluoro-2-methylquinazolin-5-ylamino)-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol(AM 2016)

150 mg (0.347 mmol) of imine is cyclized in 2.5 ml of dichloromethane at0° C. with 1 ml of titanium tetrachloride as described in Example 146.After chromatography on silica gel (mobile solventmethanol/dichloromethane), 87.1 mg (58.1%) of the desired compound isobtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.42 (3H), 1.58 (3H), 2.08-2.23 (2H), 2.87(3H), 3.79 (3H), 5.28 (1H), 6.73 (1H), 6.82 (1H), 6.99 (1H), 7.23 (1H),7.68 (1H), 9.68 (1H).

1-(8-Fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol

60 mg (0.133 mmol) of4-(3-methoxyphenyl)-1,1,1-trifluoro-2-{[8-fluoro-2-methylquinazolin-5-ylimino]-methyl}-4-methylpentan-2-olis mixed with 1.3 ml of a 1 M solution of boron tribromide indichloromethane while being cooled in an ice bath. After 45 minutes ofstirring at room temperature, the reaction mixture is mixed with ice,and saturated sodium bicarbonate solution is added drop by drop until apH of 8 is reached. The cold bath is removed, and the mixture is stirredvigorously for 15 minutes. After extraction with ethyl acetate, thecombined organic extracts are washed with water and then with brine.After drying, the solvent is spun off, and the residue ischromatographed on silica gel (mobile solvent ethyl acetate/hexane).Finally, 19.5 mg (33.5%) of the desired compound is obtained.

¹H-NMR (300 MHz, CD₃OD): δ=1.41 (3H), 1.56 (3H), 2.07-2.21 (2H), 2.89(3H), 5.24 (1H), 6.60 (1H), 6.78-6.91 (2H), 7.13 (1H), 7.59 (1H), 9.68(1H).

Example 2755-(2,6-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one5-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentylidenamino]-2H-isoquinolin-1-one

271 mg (0.936 mmol) of4-(3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal is reacted,as already described several times, with 150 mg (0.936 mmol) of5-amino-2H-isoquinolin-1-one to form imine. After chromatography, 341.1mg (84.5%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.33 (3H), 1.55 (3H), 2.39 (1H), 2.79 (1H),3.56 (3H), 4.95 (1H), 6.38-6.55 (2H), 6.78 (1H), 6.79-6.95 (2H), 7.09(1H), 7.12-7.35 (3H), 8.31 (1H), 11.09 (1H).

5-(2-Hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one

150 mg (0.347 mmol) of the above-described imine is cyclized to thedesired compound as described in Example 274 with titanium tetrachloridein dichloromethane. After chromatography, 18.8 mg (12.5%) is isolated.

¹H-NMR (300 MHz, CD₃OD): δ=1.42 (3H), 1.58 (3H), 2.05-2.24 (2H), 3.79(3H), 5.15 (1H), 6.73 (1H), 6.89 (1H), 6.96 (1H), 7.05 (1H), 7.10-7.25(2H), 7.49 (1H), 7.70 (1H).

5-(2,6-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one

90 mg (0.208 mmol) of the above-described imine is cyclized directlywith boron tribromide to the free phenol as described in Example 274.After conventional working-up and chromatography, 53.8 mg (61.7%) of thedesired compound is obtained as a diastereomer mixture at a 3:2 ratio.

MS (ES+): 419 (100%)

Example 2765-(2,6-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one5-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentylidenamino]-1H-quinolin-2-one

300 mg (1.033 mmol) of4-(3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal is reacted,as already described several times, with 165.4 mg (1.033 mmol) of5-amino-1H-quinolin-2-one to form imine. After chromatography, 414.3 mg(92.7%) of the desired compound is isolated.

¹H-NMR (300 MHz, CDCl₃): δ=1.33 (3H), 1.53 (3H), 2.40 (1H), 2.78 (1H),3.58 (3H), 4.85 (1H), 6.08 (1H), 6.49 (1H), 6.72-6.83 (2H), 6.90 (1H),7.08 (1H), 7.28-7.38 (3H), 8.18 (1H), 12.53 (1H).

5-(2-Hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one

150 mg (0.347 mmol) of the above-described imine is cyclized to thedesired compound as described in Example 274 with titanium tetrachloridein dichloromethane. After chromatography, 35.8 mg (23.8%) ofdiastereomer A is isolated, and another 14.3 mg (9.5%) as a diastereomermixture. The spectroscopic data refer to the pure diastereomer.

¹H-NMR (300 MHz, CD₃OD): δ=1.42 (3H), 1.59 (3H), 2.05-2.24 (2H), 3.80(3H), 5.18 (1H), 6.52 (1H), 6.61 (1H), 6.65-6.79 (2H), 6.95 (1H), 7.20(1H), 7.39 (1H), 8.23 (1H).

5-(2,6-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one

90 mg (0.208 mmol) of the above-described imine is cyclized directlywith boron tribromide to free phenol as described in Example 274. Afterconventional working-up and chromatography, 37.6 mg (43.1%) of thedesired compound is obtained as a diastereomer mixture in a 4:1 ratio.

MS (ES+): 419 (100%)

Example 2777-Fluoro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2.6-diol4-Bromomethyl-1-fluoro-2-methoxybenzene

41.7 g (297.54 mmol) of 2-fluoro-5-methylanisole is refluxed overnightwith 59.9 g (327.48 mmol) of N-bromosuccinimide and 145 mg of benzoylperoxide in 945 ml of carbon tetrachloride. The reaction mixture isfiltered [through] a glass-fiber filter, and after the solvent is spunoff, the residue (72.85 g>100%) is incorporated in crude form into thenext stage.

(4-Fluoro-3-methoxy-phenyl)-acetonitrile

72.85 g of the above-described bromine compound is added in a mixturethat consists of 330 ml of dimethylformamide and 209 ml of water. After32.5 g (498.86 mmol) of potassium cyanide is added at room temperature(slight heating), the batch is stirred overnight at room temperature.The reaction mixture is poured into ice water and extracted three timeswith methyl tert-butyl ether. The combined organic extracts are washedwith brine, and the solvent is spun off after drying. The residue ischromatographed on silica gel (mobile solvent ethyl acetate/hexane).33.34 g (61.4%) of the desired nitrile is isolated.

¹H-NMR (CDCl₃): 3.72 (2H), 3.93 (3H), 6.83 (1H), 6.93 (1H), 7.09 (1H).

2-(4-Fluoro-3-methoxyphenyl)-2-methylpropionitrile

16.67 g (100.93 mmol) of (4-fluoro-3-methoxyphenyl)-acetonitrile isintroduced with 30.1 g (211.96 mmol) of methyliodide into 158 ml ofdimethylformamide. At 0° C., 8.50 g (211.96 mmol) of a 55-60% sodiumhydride suspension is added in portions. After stirring overnight atroom temperature, the reaction mixture is poured into ice water and thenextracted three times with methyl tert-butyl ether. The combined organicextracts are washed with water and with brine. After the solvent isdried and spun off, the residue is chromatographed on silica gel (mobilesolvent ethyl acetate/hexane). 5.11 g (26.2%) of the desired compoundand 6.18 g of the monomethyl compound, which is realkylated, areisolated.

¹H-NMR (CDCl₃): 1.72 (6H), 3.92 (3H), 6.95 (1H), 7.00-7.12 (2H).

2-(4-Fluoro-3-methoxyphenyl)-2-methylpropionaldehyde

9.37 g (48.50 mmol) of2-(4-fluoro-3-methoxyphenyl)-2-methylpropionitrile is reduced with 39.98ml (72.48 mmol) of a 1.2 M solution of DIBAL in toluene at −78° C.,specifically as described in some preceding examples. For hydrolysis,isopropanal and tartaric acid are used. 9.31 g of a mixture that isproduced from up to a third of the starting material and two thirds ofthe desired aldehyde is isolated. This mixture is subjected again to aDIBAL reaction at −78° C. and after working-up, a mixture (9.18 g) thatconsists of nitrile, aldehyde and the corresponding alcohol exists. Thismixture is reduced another time with DIBAL, but this time at atemperature of −10 to 0° C. After undergoing hydrolysis withisopropanol, 1.45 g of the desired aldehyde and 5.68 g of thecorresponding alcohol are isolated. This alcohol is oxidized to aldehydeas already described several times under Swern conditions. Afterconventional working-up and purification, 5.09 g of the desired aldehydeis isolated.

¹H-NMR (CDCl₃): 1.48 (6H), 3.90 (3H), 6.75-6.87 (2H), 7.09 (1H), 9.49(1H).

Ethyl-(E)-(4-fluoro-3-methoxyphenyl)-4-methylpent-2-enoate

6.10 g (27.23 mmol) of triethylphosphonoacetate is dissolved in 16.5 mlof tetrahydrofuran. At 0° C., 1.49 ml (29.12 mmol) of LDA is added indrops, and the batch is stirred for 30 minutes at 0° C. After dropwiseaddition of 5.34 g (27.22 mmol) of the above-described aldehyde,dissolved in 16.5 ml of tetrahydrofuran, the reaction mixture is stirredovernight at room temperature. At 0° C., water is carefully added indrops, stirred vigorously for ten minutes and then shaken three timeswith methyl tert-butyl ether. The combined organic extracts are washedwith brine and dried. After the solvent is spun off, the residue ischromatographed on silica gel (mobile solvent ethyl acetate/hexane).5.75 g (79.3%) of the desired compound is isolated.

¹H-NMR (CDCl₃): 1.29 (3H), 1.48 (6H), 3.90 (3H), 4.20 (2H), 5.80 (1H),6.79-6.90 (2H), 7.02 (1H), 7.10 (1H).

Ethyl-(4-fluoro-3-methoxyphenyl)-4-methylpentanoate

5.75 g (21.59 mmol) ofethyl-(E)-(4-fluoro-3-methoxyphenyl)-4-methylpent-2-enaote ishydrogenated in 80 ml of ethanol with the aid of 307.3 mg of PdC (10%)overnight in hydrogen atmosphere. The reaction mixture is suctioned offthrough a glass-pleated filter, and the solvent is spun off. 5.69 g(98.3%) of the desired compound, which is further incorporated in crudeform, is isolated.

¹H-NMR (CDCl₃): 1.22 (3H), 1.31 (6H), 1.90-2.10 (4H), 3.90 (3H), 4.08(2H), 6.83 (1H), 6.91 (1H), 7.00 (1H).

Ethyl-4-(4-fluoro-3-methoxyphenyl)-2-hydroxy-4-methylpentanoate

5.69 g (21.21 mmol) ofethyl-(4-fluoro-3-methoxyphenyl)-4-methylpentanoate is reacted with 7.76g (26.70 mmol) of Davis reagent as described in Example 273. Accordingto the working-up and chromatography on silica gel (mobile solvent ethylacetate/hexane) that are described there, 2.98 g (49.5%) of the desiredcompound is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.29 (3H), 1.40 (3H), 1.48 (3H), 1.83 (1H),2.20 (1H), 2.56 (1H), 3.85-3.99 (4H), 4.13 (2H), 6.90 (1H), 6.95-7.08(2H).

Ethyl-4-(4-fluoro-3-methoxyphenyl)-4-methyl-2-oxopentanoate

2.78 g (9.78 mmol) ofethyl-4-(4-fluoro-3-methoxyphenyl)-2-hydroxy-4-methylpentanoate isoxidized in Example 273 with SO₃/Py in dichloromethane to thecorresponding a ketoester. After chromatography on a Flashmaster, 2.48 g(89.9%) of the desired compound is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.28 (3H), 1.48 (6H), 3.15 (2H), 3.90 (3H),4.12 (2H), 6.88 (1H), 6.90-7.03 (2H).

4-(4-Fluoro-3-methoxyphenyl)-2-hydroxy-4-methylphenyl)-2-(trifluoromethyl)-pentanal

2.48 g (8.79 mmol) ofethyl-4-(4-fluoro-3-methoxyphenyl)-4-methyl-2-oxopentanoate is convertedinto aldehyde via the sequence described in Example 273 oftrifluoromethylation with Rupperts reagent, reduction of ester withlithium aluminum hydride to alcohol and subsequent oxidation of alcoholaccording to Swern. 382.3 mg of the desired aldehyde is ultimatelyisolated over the three stages.

¹H-NMR (300 MHz, CDCl₃): δ=1.38 (3H), 1.48 (3H), 2.32 (1H), 2.66 (1H),3.68 (1H), 3.90 (3H), 6.80-6.92 (2H), 7.02 (1H), 8.88 (1H).

1,1,1-Trifluoro-4-(4-fluoro-3-methoxyphenyl)-2-[(8-fluoro-2-methylquinazolin-5-ylimino)-methyl]-4-methylpentan-2-ol

127.4 mg (0.413 mmol) of4-(4-fluoro-3-methoxyphenyl)-2-hydroxy-4-methylphenyl)-2-(trifluoromethyl)-pentanalis reacted with 73.2 mg (0.413 mmol) of 8-fluoro-2-methylquinazoline and235.1 mg (0.827 mmol) of titanium(IV) isopropylate in 2.2 ml of xyleneas already described several times to form the corresponding imine.After chromatography on a Flashmaster, 138.5 mg (71.7%) of the desiredcompound is isolated.

¹H-NMR (CDCl₃): δ=1.35 (3H), 1.56 (3H), 2.44 (1H), 2.72 (1H), 2.99 (3H),3.68 (3H), 4.77 (1H), 6.38 (1H), 6.70-6.90 (3H), 7.38-7.48 (2H), 9.65(1H).

7-Fluoro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol

20 mg (0.043 mmol) of the above-described imine is reacted with 0.6 mlof boron tribromide (1 M solution in dichloromethane) at 0° C. and thusconverted into the cyclized phenol. After chromatography on aFlashmaster, 7.1 mg (36.6%) is isolated.

¹H-NMR (CD₃OD)=1.41 (3H), 1.56 (3H), 2.06-2.22 (2H), 2.89 (3H), 5.24(1H), 6.84 (1H), 6.89-7.04 (2H), 7.59 (1H), 9.69 (1H).

Example 2785-[7-Fluoro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one5-[4-(4-Fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidenamino]-1H-quinolin-2-one

127 mg (0.413 mmol) of the aldehyde that is described in Example 277 isreacted as described there with 66.32 mg (0.413 mmol) of5-amino-1H-quinolin-2-one to form imine.

After chromatography on a Flashmaster, 89.2 mg (47.9%) of the desiredcompound is isolated.

¹H-NMR (CDCl₃): δ=1.37 (3H), 1.53 (3H), 2.43 (1H), 2.71 (1H), 3.71 (3H),4.85 (1H), 6.10 (1H), 6.70-6.92 (4H), 7.30-7.42 (3H), 8.15 (1H), 12.42(1H).

5-[7-Fluoro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one

89.2 mg (0.198 mmol) of the above-described imine is reacted in 1.9 mlof dichloromethane with 1.3 ml (1.188 mmol) of titanium tetrachloride toform cyclic ether. After chromatography on a Flashmaster, 5.7 mg of thedesired compound is obtained.

¹H-NMR (CDCl₃): δ=1.40 (3H), 1.60 (3H), 2.00-2.29 (2H), 3.88 (3H), 5.00(1H), 5.07 (1H), 5.68 (1H), 6.45-6.60 (3H), 6.85-7.02 (2H), 7.32 (1H),8.20 (1H), 10.05 (1H).

Example 2796-Fluoro-1-[(2-methylquinolin-5-yl)amino]-4-ethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol

¹H-NMR (300 MHz, CD₃OD): δ=0.97 (s, 3H), 1.79 (qdd, 1H), 1.96 (qdd, 1H),2.19 (dd, 1H), 2.36 (dd, 1H), 2.73 (s, 3H), 3.40 (m, 1H), 4.98 (d, 1H),5.12 (d, 1H), 6.60 (d, 1H), 6.89 (d, 2H), 7.23 (d, 1H), 7.43 (d, 1H),7.51 (t, 1H), 8.11 (d, 1H).

Examples 280 and 2815-{[7-Bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-oneDiastereomer A and5-{[7-Bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one,Diastereomer B

Analogously to Example 10, the corresponding imine is produced startingfrom 800 mg of4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 348 mg of 5-amino-quinolin-2(1H)-one. 16 mg of diastereomer A of5-{[7-bromo-2-,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one(fraction A) and 79 mg of diastereomer B of5-{[7-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-oneare obtained by reaction of 800 mg of imine with 7.9 ml of borontribromide solution (1H in dichloromethane).

Fraction A: ¹H-NMR (CD₃OD): δ=1.40 (s, 3H), 1.55 (s, 3H), 1.90 (d, 1H),2.25 (d, 1H), 5.22 (s, 1H), 6.11 (d, 1H), 6.58 (d, 1H), 6.67 (d, 1H),7.12-7.30 (m, 3H), 8.20 (d, 1H).

Fraction B: ¹H-NMR (CD₃OD): δ=1.54 (s, 3H), 1.65 (s, 3H), 2.05 (d, 1H),2.14 (d, 1H), 5.13 (s, 1H), 6.53 (d, 1H), 6.62 (d, 1H), 6.72 (d, 1H),6.87 (s, 1H), 6.94 (s, 1H), 7.40 (t, 1H), 8.22 (d, 1H).

Example 2821,6-Dihydroxy-8,8-dimethyl-5-(1-oxo-1,2-dihydroisoguinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

75 mg (0.166 mmol) of5-(6-chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalin-1-ylamino)-2H-isoquinolin-1-oneis dissolved in 1.3 ml of 1-methyl-2-pyrrolidinone and reacted in themicrowave with 16.27 mg (0.332 mmol) of sodium cyanide and 36.27 mg(0.166 mmol) of nickel(II) bromide as described in Example 160. Theblack reaction mixture is added through a glass-fiber filter. Afterwashing with ethyl acetate, the filtrate is mixed with an additional 60ml of ethyl acetate. It is shaken with water and with brine. Afterdrying, the solvent is spun off, and the residue is chromatographed onsilica gel (amine plate: mobile solvent methanol/dichloromethane). 16.2mg (22.1%) of the desired nitrile is isolated.

MS (ES+): 444 (100%); IR (microscope, matrix: diamond): 2230.

The entire disclosures of all applications, patents and publications,cited herein and of corresponding German Application No. 103 47 383.1,filed Oct. 8, 2003, are incorporated by reference herein.

1. Compounds of general formula (I),

in which R¹ and R², independently of one another, mean a hydrogen atom,a hydroxy group, a halogen atom, an optionally substituted(C₁-C₁₀)-alkyl group, an optionally substituted (C₁-C₁₀)-alkoxy group, a(C₁-C₁₀)-alkylthio group, a (C₁-C₅)-perfluoroalkyl group, a cyano group,or a nitro group, or R¹ and R² together mean a group that is selectedfrom the groups —O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, —O—CH═CH—,—(CH₂)_(n+2)—, —NH—(CH₂)_(n+1), N(C₁-C₃-alkyl)-(CH₂)_(n+1), or—NH—N═CH—,  whereby n=1 or 2, and the terminal oxygen atoms and/orcarbon atoms and/or nitrogen atoms are linked to directly adjacentring-carbon atoms, or NR⁸R⁹,  whereby R⁸ and R⁹, independently of oneanother, can be hydrogen, C₁-C₅-alkyl or (CO)—C₁-C₅-alkyl, R³ means aC₁-C₁₀-alkyl group that optionally is substituted by 1-3 hydroxy groups,halogen atoms, 1-3 (C₁-C₅)-alkoxy groups, an optionally substituted(C₃-C₇)-cycloalkyl group, an optionally substituted heterocyclyl group,an optionally substituted aryl group, a monocyclic or bicyclicheteroaryl group that optionally contains 1-4 nitrogen atoms and/or 1-2oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups and thatoptionally is substituted by one or more groups selected from(C₁-C₅)-alkyl groups (which optionally can be substituted by 1-3 hydroxygroups or 1-3 COOR¹³ groups, whereby R¹³ means hydrogen or a C₁-C₅-alkylgroup); (C₁-C₅)-alkoxy groups, halogen atoms, hydroxy groups, NR⁸R⁹groups, exomethylene groups, or oxygen, whereby this group can be linkedvia any position to the amine of the tetrahydronaphthalene system andoptionally can be hydrogenated at one or more locations, R⁴ means ahydroxy group, a group OR¹⁰, or an O(CO)R¹⁰ group, whereby R¹⁰ means anyhydroxy protective group or a C₁-C₁₀-alkyl group, R⁵ means a(C₁-C₁₀)-alkyl group or an optionally partially or completelyfluorinated (C₁-C₁₀)-alkyl group, R⁶ and R⁷, independently of oneanother, mean a hydrogen atom, a methyl or ethyl group or together withthe carbon atom of the tetrahydronaphthalene system mean a(C₃-C₆)-cycloalkyl ring.
 2. Stereoisomers of general formula (I),

in which R¹ and R², independently of one another, mean a hydrogen atom,a hydroxy group, a halogen atom, a (C₁-C₁₀)-alkyl group, a(C₁-C₁₀)-alkoxy group, a (C₁-C₁₀)-alkylthio group, a(C₁-C₅)-perfluoroalkyl group, a cyano group, or a nitro group, or R¹ andR² together mean a group that is selected from the groups—O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, —O—CH═CH—, —(CH₂)_(n+2)—,—NH—(CH₂)_(n+1), —N(C₁-C₃-alkyl)-(CH₂)_(n+1), and —NH—N═CH—,  wherebyn=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/ornitrogen atoms are linked to directly adjacent ring-carbon atoms, orNR⁸R⁹,  whereby R⁸ and R⁹, independently of one another, can behydrogen, C₁-C₅-alkyl or (CO)—C₁-C₅-alkyl, R³ means a C₁-C₁₀-alkyl groupthat optionally can be substituted by 1-3 hydroxy groups, halogen atoms,or 1-3 (C₁-C₅)-alkoxy groups, an optionally substituted(C₃-C₇)-cycloalkyl group, an optionally substituted heterocyclyl group,an optionally substituted aryl group, a monocyclic or bicyclicheteroaryl group that optionally contains 1-3 nitrogen atoms and/or 1-2oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups and thatoptionally is substituted by one or more groups that are selected from(C₁-C₅)-alkyl groups (which optionally can be substituted by 1-3 hydroxygroups or 1-3 COOR⁶ groups); (C₁-C₅)-alkoxy groups, halogen atoms, orexomethylene groups, whereby this group can be linked via any positionto the amine of the tetrahydronaphthalene system and optionally can behydrogenated at one or more locations, R⁴ means a hydroxy group, or agroup OR¹⁰,  whereby R¹⁰ means a C₁-C₁₀-alkyl group, R⁵ means a(C₁-C₅)-alkyl group or an optionally partially or completely fluorinated(C₁-C₅)-alkyl group, R⁶ and R⁷, independently of one another, mean ahydrogen atom, a methyl or ethyl group or together with the carbon atomof the tetrahydronaphthalene system mean a (C₃-C₆)-cycloalkyl ring. 3.Stereoisomers of general formula (I),

in which R¹ and R², independently of one another, mean a hydrogen atom,a hydroxy group, a halogen atom, a (C₁-C₁₀)-alkyl group, a(C₁-C₁₀)-alkoxy group, a (C₁-C₁₀)-alkylthio group, a(C₁-C₅)-perfluoroalkyl group, a cyano group, or a nitro group, or R¹ andR² together mean a group that is selected from the groups—O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, —O—CH═CH—, or —(CH₂)_(n+2)—, whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms arelinked to directly adjacent ring-carbon atoms, or NR⁸R⁹,  whereby R⁸ andR⁹, independently of one another, can be hydrogen, C₁-C₅-alkyl or(CO)—C₁-C₅-alkyl, R³ means a C₁-C₁₀-alkyl group that optionally can besubstituted by 1-3 hydroxy groups, halogen atoms, an optionallysubstituted phenyl group, a monocyclic or bicyclic heteroaryl group thatcontains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfuratoms and that optionally is substituted by 1-2 keto groups, 1-2(C₁-C₅)-alkyl groups, 1-2 (C₁-C₅)-alkoxy groups, 1-3 halogen atoms, or1-2 exomethylene groups, whereby these groups can be linked via anyposition to the amine of the tetrahydronaphthalene system and optionallycan be hydrogenated at one or more locations, R⁴ means a hydroxy group,R⁵ means a (C₁-C₅)-alkyl group or an optionally partially or completelyfluorinated (C₁-C₅)-alkyl group, R⁶ and R⁷, independently of oneanother, mean a hydrogen atom, a methyl or ethyl group, or together withthe carbon atom of the chain mean a (C₃-C₆)-cycloalkyl ring. 4.Stereoisomers of general formula (I),

in which R¹ and R², independently of one another, mean a hydrogen atom,a hydroxy group, a halogen atom, a (C₁-C₅)-alkyl group, a (C₁-C₅)-alkoxygroup, or R¹ and R² together mean a group that is selected from thegroups —O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, —O—CH═CH—, or —(CH₂)_(n+2)—,whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms arelinked to directly adjacent ring-carbon atoms, R³ means a C₁-C₁₀-alkylgroup that optionally can be substituted by 1-3 hydroxy groups, halogenatoms, a phenyl, phthalidyl, isoindolyl, dihydroindolyl,dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl,phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl,indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl,phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl,dihydroisoindolonyl, benzimidazole or indolyl group that optionally issubstituted with C₁-C₅-alkyl, halogen, hydroxy, or C₁-C₅-alkoxy, wherebythese groups can be linked via any position to the amine of thetetrahydronaphthalene system and optionally can be substituted in one ormore places with 1-2 keto groups, 1-2 (C₁-C₃)-alkyl groups, 1-2 (C₁-C₃)—alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups, andoptionally can be hydrogenated at one or more locations, R⁴ means ahydroxy group, R⁵ means a (C₁-C₅)-alkyl group, or an optionallypartially or completely fluorinated (C₁-C₅)-alkyl group, R⁶ and R⁷,independently of one another, mean a hydrogen atom, a methyl or ethylgroup or together with the carbon atom of the tetrahydronaphthalenesystem mean a (C₃-C₆)-cycloalkyl ring.
 5. Stereoisomers of generalformula (I),

in which R¹ and R², independently of one another, mean a hydrogen atom,a hydroxy group, a halogen atom, a (C₁-C₅)-alkyl group, a (C₁-C₅)-alkoxygroup, or together a (C₁-C₂)-alkylenedioxy group, whereby then R¹ and R²must be directly adjacent, R³ means a a phenyl, phthalidyl, isoindolyl,dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl,benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl,isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl,cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl,dihydroisoindolonyl, benzimidazole or indolyl group that optionally issubstituted with C₁-C₅-alkyl, halogen, hydroxy, or C₁-C₅-alkoxy, wherebythese groups can be linked via any position to the amine of thetetrahydronaphthalene system, and optionally can be substituted in oneor more places with 1-2 keto groups, 1-2 (C₁-C₃)-alkyl groups, or 1-2exomethylene groups, and optionally can be hydrogenated at one or morelocations, R⁴ means a hydroxy group, R⁵ means a (C₁-C₅)-alkyl group oran optionally partially or completely fluorinated (C₁-C₅)-alkyl group,R⁶ and R⁷, independently of one another, mean a hydrogen atom, a methylor ethyl group, or together with the carbon atom of thetetrahydronaphthalene system mean a (C₃-C₆)-cycloalkyl ring.
 6. Use ofthe stereoisomers according to one of the preceding claims for theproduction of a pharmaceutical agent.
 7. Use of the stereoisomers ofclaims 1-5 for the production of a pharmaceutical agent for treatinginflammatory diseases.
 8. Pharmaceutical preparations that contain atleast one stereoisomer according to claims 1-5 or mixtures thereof aswell as pharmaceutically compatible vehicles.
 9. Process for theproduction of the stereoisomers of general formula I, characterized inthat stereoisomers of general formula II

in which R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ have the above-mentionedmeanings, are cyclized optionally either without additional reagent, ina solvent or concentrated organic acid, or with the addition ofinorganic or organic acids or Lewis acids.
 10. Stereoisomers of generalformula I, according to one of claims 1-5, in the form of salts withphysiologically compatible anions.
 11. Stereoisomers of general formulaI, according to one of claims 1-5, whereby radical R⁵ stands for acompletely fluorinated (C₁-C₅)-alkyl group.
 12. Stereoisomers of generalformula I, according to one of claims 1-5, whereby radical R⁵ stands forthe trifluoromethyl group or the pentafluoroethyl group.